brief notes on Quinolones and Fluoroquinolones

1. QUINOLONES AND
FLOUROQUINOLONES
DR LINUS WAFULA,JKUAT.
JUNE 2021.

2. QUINOLONES AND FLOUROQUINOLONES
• Introduction
• A group of synthetic antibacterial agents mainly effective
against gram negative organisms
• Nalidixic acid first member introduced in 1964 for urinary and
GIT infections
• Synthetic fluorinated analogs of nalidixic acid: are
fluoroquinolones (FQs) with extended spectrum and systemic
effects in 1980s.
• FQs are BACTERICIDAL, act by interfering with DNA
replication. Since then many synthesized with useful spectrum.
8/24/2021 DR WAF JUNE 2021 2

3. Nalidixic acid
• The first quinolone, nalidixic acid, was isolated as a by-product
of the synthesis of chloroquine
• Less potent ,limited spectrum Active against gram negative
bacteria – E.coli, Proteus, Klebsiella, Enterobacter, Shigella
• Inhibits bacterial DNA gyrase, Bactericidal Resistance develops
rapidly
• Pharmacokinetics: Absorbed orally Metabolized in liver, highly
protein bound, excreted in urine, half life – 8 hrs.
• Concentration in urine is lethal to common urinary pathogens
(20 – 50 times that in plasma) Quinolones
8/24/2021 DR WAF JUNE 2021 3

4. • Nalidixic acid Adverse effects :
• GI upset, rashes Neurological toxicity (in children) – headache,
vertigo, drowsiness, visual disturbances, seizures
• Hemolysis in G6PD deficiency
• Indication:
• Urinary antiseptic
• Diarrhoea caused by E.coli, Proteus, Shigella, Salmonella
Ampicillin resistant Shigella enteritis (cont..,) Quinolones
8/24/2021 DR WAF JUNE 2021 4

5. QUINOLONES.
• 2 Quinolones are synthetic antimicrobials having a quinolone
structure. • Active against gram-ve bacteria, newer fluorinated
compounds also inhibit gram +ve bacteria.
• • First member was nalidixic acid introduced in 1960’s
• • Their usefulness is limited to urinary and GI tract infections
because of
• Low potency
• Modest blood and tissue levels
• Limited spectrum
• High frequency of bacterial resistance
8/24/2021 DR WAF JUNE 2021 5

6. 8/24/2021 DR WAF JUNE 2021 6

7. MODE OF ACTION.
In gram negative bacteria – Inhibition of DNA gyrase enzyme
(Inhibit negative super coiling)
In gram positive bacteria – •Inhibition of Topoisomerase IV –
Inhibition of nicking and separation of daughter DNA strands after
DNA replication
•The malformed DNA is digested by Exoneucleases Mechanism
of Action
8/24/2021 DR WAF JUNE 2021 7

8. 8/24/2021 DR WAF JUNE 2021 8

9. Mechanism of action.
• DNA- Enzyme- . The gyrase is composed of two A subunits
and two B subunits.
• The A subunits can cut one of double strands of the DNA
• .This is an ATP- dependent reaction. The energy is provided by
B units.
• . FQs are inhibitor of A subunits.
• Therefore, the action of gyrase is inhibited and DNA replication
or transcription is blocked as result of the death of bacteria.
8/24/2021 DR WAF JUNE 2021 9

10. 8/24/2021 DR WAF JUNE 2021 10

11. Mechanism of Resistance to Quinolones
& FQ.
• Due to
• 1. a) One or more point mutations in the quinolone binding
region of the target enzyme
b) A change in the permeability of the organism
2. DNA gyrase is the primary target in E coli, with single-step
mutants exhibiting amino acid substitution in the A subunit of
gyrase
3.Topoisomerase Ⅳ is a secondary target in E coli that is
altered in mutants expressing higher levels of resistance.
8/24/2021 DR WAF JUNE 2021 11

12. 4.In staphylococci and streptococci, the situation is reversed,
topoisomerase Ⅳ is the primary target, and gyrase is the
secondary target.
5.Resistance to one fluoroquinolone, particularly if of high level,
generally confers cross-resistance to all other members of this
class.
8/24/2021 DR WAF JUNE 2021 12

13. General features of FQs
• Rapidly bactericidal & high potency
• Long post antibiotic effect on pseudomonas &
enterobacteriaceae
Attain high levels in body fluids & tissues
• Diarrhea and antibiotic-associated colitis unusual
• Low frequency of mutational resistance
Active against many β-lactam & aminoglycoside resistant
bacteria
Less active at acidic pH
8/24/2021 DR WAF JUNE 2021 13

14. Classification of FQs First generation.
1. Introduced in 1980 with one fluoro substitution Norfloxacin
Ciprofloxacin Ofloxacin (only as ophthalmic in the United
States) Pefloxacin
2. Second-generation: In 1990s with additional fluoro & other
substitution extending antimicrobial spectrum to gram positive
bacteria ,anaerobes and longer half life.
3.Levofloxacin, Moxifloxacin, Gemifloxacin, Prulifloxacin,
Lomefloxacin, Sparfloxacin, Finafloxacin .
8/24/2021 DR WAF JUNE 2021 14

15. 8/24/2021 DR WAF JUNE 2021 15

16. Pharmacokinetics of FQs:
• Prototype : Ciprofloxacin • Oral given, well absorbed, be impaired
by divalent cations, including those in antacid
• Distributed widely in body fluids and tissues but CSF & aqueous
levels are low
• Urinary & billiary concentrations are 10-50 fold higher than plasma
• Less active in acidic pH
• Pass placenta reach to the fetus,
• Biotransformation of the drugs in the liver
• Most eliminated by renal, either tubular secretion or glomerular
filtration.
8/24/2021 DR WAF JUNE 2021 16

17. Therapeutic applications of FQs.
• Fluoroquinolones are extensively used treating general
infection.
• a. Urinary tract infections, even when caused by multidrug-
resistant bacteria: cystitis, prostatitis,pyelonephritis.
• b. Intestinal and biliary tract infections
• c. skin and Soft tissue infections, infected skin ulcers and
burns.
• d. Bone, joint and intra-abdominal infections
• e. Respiratory tract infections: empyema, pneumonia, lung
abcess.
8/24/2021 DR WAF JUNE 2021 17

18. Uses
• Bacterial Meningitis
• Enteric fever, caused by Salmonelle spp
• Bacterial Diarrhoeal diseases caused by campylobacter, shigella
• Gonorrhea and chancroid
• Conjuctivitis
• Tuberculosis
8/24/2021 DR WAF JUNE 2021 18

19. CIPROFLOXACIN
• prototype): Highly effective against pseudomonas •
• Drug of choice for prophylaxis & treatment of Anthrax & prophylaxis
of meningococcal meningitis.
• Typhoid
• UTIs • Bacterial gastroenteritis • Osteomyelitis & joint infections •
Gonorrhea & chanchroid • Septicemia due to gram negative
organisms •
• Respiratory infections especially due to Mycoplasma, H. influenza,
Legionella • Prophylaxis of infections in neutropenic & cancer
patients •
• Topical use: conjunctivitis Unique features of different FQs.
8/24/2021 DR WAF JUNE 2021 19

20. NORFLOXACIN
• Minimum oral bioavailability •
• Minimum Inhibitory concentration for gram negative bacteria is
8-10 times higher than that of ciprofloxacin.
• Attains lower concentration in tissues
Less potent than ciprofloxacin
Primarily used in urinary & genital tract infections
For bacterial diarrheas it is good as anaerobic flora of the gut not
affected. Unique features of different FQs.
8/24/2021 DR WAF JUNE 2021 20

21. Unique features of different FQs
PEFLOXACIN:
• Methyl derivative of Norfloxacin
Completely absorbed, exhibits cumulation on repeated absorbtion
• More lipid soluble, CSF concentration are higher than other FQs •
Highly metabolized in liver to active metabolite
• Dose needs to be reduced in liver disease but not in renal
insufficiency
• Preferred for meningeal infections
• 200,400mg tablet available & injection 400mg/5ml to be used diluted
in glucose solution but not in saline as it precipitates in presence of
Chloride ions.
8/24/2021 DR WAF JUNE 2021 21

22. Unique features of different FQs
OFLOXACIN:
• Lipid soluble oral bioavailability is high
• Food does not interfere its absorption
Oral tablet (200 & 400mg) & i.v.(200mg)
Largely excreted unchanged by kidney ,so dose need reduced in
renal failure
Effective for gonococcal infection, including disseminated disease.
• Occasionally used for treatment of tuberculosis and atypical
mycobacterial infections
• Suitable for eradication of meningococcal infections from carriers.
• Highly effective in: leprosy, Chlamydial urethritis or cervicitis ,
atypical (Mycoplasma) pneumonia & Chronic bronchitis (cont..,)
8/24/2021 DR WAF JUNE 2021 22

23. SPARFLOXACIN.
• Excreted by both renal & hepatic Long half life
• Increased action against gram positive bacteria, Streptococcus,
Staphylococcus, Enterococcus,Anaerobes & mycobacteria
• NOT effective against Peudomonas
• Indication: upper and lower respiratory tract infections. Highly
effective in Tuberculosis, , Macobacterium Avium Complex,
Leprosy
• Adverse effects: Phototoxic QT prolongation (cont..,)
8/24/2021 DR WAF JUNE 2021 23

24. MOXIFLOXACIN
• Hepatic metabolism & biliary excretion Tablet & intravenous
(400 mg) Indications: MDR tuberculosis, Bronchitis, pneumonia,
otitis media, Urinary concentrations are low not suitable for UTI
• Contraindications : Primarily metabolised in liver, not used in
liver disease Patients with Seizures & Patients receiving
proarrythmic drugs as it prolong Q-T interval.
8/24/2021 DR WAF JUNE 2021 24

25. LEVOFLOXACIN:
• L-isomer of ofloxacin
• Maximum oral bioavailablity, given orally or i.v.
• Excreted unchanged by kidney Indications :
• Upper and lower respiratory tract infections. Community
acquired pneumonia :
• (Respiratory FQ) MDR TB, nosocomial infections Eye drops for
bacterial conjunctivitis & corneal ulcer. (cont..,)
8/24/2021 DR WAF JUNE 2021 25

26. LOMEFLOXACIN
• Similar to Ciprofloxacin ,more active against Gram negative
bacilli & chlamydia Longer plasma half life ,once daily
administration 400 mg tablet available & Topical eye drops
available (0.3%) Side effect:
• Photo toxicity & Q-T prolongation Withdrawn in USA & other
countries, available in India (cont..,)
8/24/2021 DR WAF JUNE 2021 26

27. 8/24/2021 DR WAF JUNE 2021 27

28. WITHDRAWN FROM THE MARKET
• Due to adverse effects like
• Gatifloxacin: QT prolongation & dysglycemia (increase or
decrease blood sugar level: risky in diabetics) withdrawn from
market.
• Temafloxacin: immune hemolytic anemia
• Grepafloxacin: cardiotoxicity: QT prolongation
• Clinafloxacin : phototoxicity
8/24/2021 DR WAF JUNE 2021 28

29. SIDE EFFECTS.
• The most common effects are
• a) nausea, vomiting, and diarrhea.
• b) Headache, dizziness, insomnia, skin rash, occasionally.
• c). Photosensitivity occurs with lomefloxacin and pefloxacin.
• d). FQs may damage growing cartilage and cause an arthropathy.
• They are not used in patients under 18years of age.
• The arthropathy is reversible.
• e) FDA has issued warning regarding peripheral neuropathy
• f) Ciprofloxacin prophylaxis use in anthrax patients associated with
damage to muscle ligament.
8/24/2021 DR WAF JUNE 2021 29

30. Drug interactions
• Complexation with metallic ions (Fe, Al, Mg, Ca & Zn) - Common to
all fluoroquinolones. - Chelation complexes provides the basis for
their incompatibilities with antacids, hematinics, and mineral
supplements containing divalent or trivalent metals
• CYP1A2 inhibition: increase the levels of theophylline, warfarin &
caffeine; especially by ciprofloxacin & pefloxacin ( Lomefloxacin,
Levofloxacin & Sparfloxacin have no effect )
• NSAIDS: increase CNS toxicity of FQs; seizures may occur
• FQs which prolong QTs interval should be used with caution those
receiving class 1A, class III antiarrhythmic; erythromycin, TCAs etc.
8/24/2021 DR WAF JUNE 2021 30

31. Contraindications & precautions
• Patients with seizures
• Pregnancy & lactation
• Children below 18 years
• Drugs prolonging QT interval are contraindicated in patients of
cardiac arrhythmia & in hypokalemia
• Hepatic & renal failure
8/24/2021 DR WAF JUNE 2021 31

32. • THANK YOU.
8/24/2021 DR WAF JUNE 2021 32