Quinolones, fluoroquinolones drugs

1. 1
QUINOLONES,
FLUOROQUINOLONES
Eric Uwiduhaye, MPS

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MECHANISMS
• Inhibitors of Nucleic Acid Synthesis
• DNA Damaging Agents
• Inhibitors of Cell Wall Synthesis
• Cell Membrane Damaging Agents
• Inhibitors of Protein Synthesis

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DNA GYRASE & DNA TOPOISOMERASE IV
INHIBITORS
GRAM-: GYRASE
GRAM+: TOPO IV

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QUINOLONES
• Spectrum: Nalidixic: Gram -/+
Ciprofloxacin: Wider Gram -/+
-Anti-pseudomonal
• Clinical Uses: UTI, RTI, Tuberculosis
Resistance is common-various mechanisms
• PK: A: Oral-good
D: Wide; []’d in urine, prostatic fluid
M: Liver-oxidation, demethylation
E: Renal, rapid clearance (T1/2=4 h)
T: Slight GI, Nausea/Vomiting (NV)

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QUINOLONES, FLUOROQUINOLONES &
OTHER DRUGS USED FOR UTIs
Quinolones
 Nalidixic acid only useful for the
 Cinoxacin treatment of lower UTIs
Fluoroquinolones
 Norfloxacin
 Ciprofloxacin
 Enoxacin
 Lomefloxacin
 Ofloxacin
 Pefloxacin

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Quinolones and fluoroquinolones have the
same mechanism of antibacterial action
Quinolones do not achieve systemic
antibacterial levels.
Fluorinated derivatives have improved
antibacterial activity, achieve bactericidal
levels in blood and tissues
Quinolones and fluoroquinolones

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Mechanism of Action
Inhibits a subunit of DNA gyrase (also
known as bacterial topoisomerase II) and
topoisomerase IV.
Inhibition of DNA gyrase prevents the relaxation
of positively supercoiled DNA that is required
for normal transcription and replication
inhibition of DNA synthesis
BACTERICIDAL EFFECT
Inhibition of topoisomerase IV interference
with separation of replicated chromosomal DNA
into daughter cells during cell division

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Spectrum of Action
&
Pharmacokinetics

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Quinolones
Nalidixic acid
Cinoxacin
Effective against enteric Gram negatives, not against
Pseudomonas
P.O.: 1 g qid x 7 days; 500 mg qid (chronic infections)
Child > 3 months: max 50 mg/ke daily
This prodrug is hydroxylated to a bactericidal
metabolite which is concentrated in the urine
> 90% plasma protein bound
Cinoxacin shows a lower incidence of resistance than
nalidixic acid

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Fluoroquinolones
Spectrum: Broad coverage. Effective vs. gram
+, gram -, atypicals (Chlamydia, Mycobacteria,
Legionella), and Pseudomonas.
 Respiratory quinolones (levofloxacin): active vs. Group
A Streptococcus (GAS), S. pneumo (including penicillin-
resistant forms), S. aureus (including MRSA), H. influ.,
and M. catarrhalis (including penicillin-resistant strains).
 Antipseudomonas quinolones (ciprofloxacin): effective
vs. Pseudomonas and gram-negative bacteria.
 Ciprofloxacin: moderate activity vs Gram +ve bacteria
(e.g. Streptococcus pneumoniae, Enterobacter faecalis)
 Not drug of first choice for pneumococcal pneumonia.
 Anaerobic organisms are not susceptible.
 New floxins (Gati, Moxi, Gemi): similar to respiratory
quinolones but less activity vs. Pseudomonas and
addition of anaerobic activity

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Pharmacokinetics
PO = IV. Once/day dosing.
Wide distribution (CSF, saliva, bone,
cartilage).
Renal excretion. Reduce dose with renal
insufficiency.
• Absorption of all fluoroquinolones is
reduced by antacids and iron pills.

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Clinical Use
To treat infections of
 lower respiratory tract (not pneumococcal
pneumonia)
 urinary tract
 infectious diarrhea, typhoid fever
 gonorrhea
 bone, joints
 septicaemia
 skin & soft tissues (high incidence of Staph
resistance: avoid in MRSA infections)

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NORFLOXACIN
 Improved gram – coverage; but is the least
active of the fluoroquinolones.
 Effective against P. aeruginosa, N. gonorrhea,
some gram +
 PO
 Urine levels are high, serum level low, NOT
USEFUL for infections outside the urinary tract
 Metabolised and excreted in bile and urine.
Reduce dose with renal insufficiency

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OFLOXACIN
 Similar to Norfloxacin. Covers additional
Pseudomonas and several Streptococci.
 PO or IV
 Clinical use:
– UTIs: 200-400 mg qd
– Upper UTIs 400mg bd
– Lower RTIs
– Skin & soft tissues infections
– Uncomplicated gonorrhea
– Non gonococcal urethritis & cervicitis
– Septicaemia
– Severe & complicated infections: 400 mg bd

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Ciprofloxacin and ofloxacin have the
broadest spectrum and widest distribution

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GREPAFLOXACIN active vs gram + & -
LEVOFLOXACIN greater activity vs pneumococci
than ciprofloxacin
LOMEFLOXACIN
 Slightly lower spectrum than Norfloxacin, otherwise is
similar
ENOXACIN
 Narrowest spectrum of the fluoroquinolones. Fails to
cover Staph. Aureus
 PO
 Penetrates kidney, fallopian tubes, prostate.
 Metabolites inhibit P-450 enzyme system and decrease
the metabolism of other drugs

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Adverse effects
Most common
 Nausea, vomiting, diarrhea, abdominal pain
 Rash, pruritus. toxic epidermal necrolysis;
rarely Steven Johnson syndrome
Less Frequent
 Hypersensitivity reactions, photosensitivity
 Blood disorders: eosinophilia, leucopenia,
thrombocytopenia
 Disturbances in vision, taste, hearing, smell.
 Drowsiness, restlessness, depression,
confusion,hallucinations, convulsions

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Adverse effects (ii)
 Occasionally, headache, dizziness, insomnia
 Fluoroquinolones damage growing cartilage,
cause arthropathy  not routinely recommended
for patients under 18 y of age.
 Fluoroquinolones are excreted into breast milk,
are contraindicated for nursing mothers
 Avoid in pregnancy
 Displaces oral anticoagulants from plasma
proteins
 Increase serum theophylline levels when given
concomitantly, may lead to seizures

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Adverse effects (iii)
Discontinue drug
 If psychiatric, neurological of
hypersensitivity reactions (including
severe rash) occur
 At first sign of pain or inflammation, rest
affected limbs until symptoms have
resolved.

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Fluoroquinolones
1. Inhibit or interfere with bacterial DNA-
gyrase & DNA topoisomerase IV:
preventing DNA synthesis.
2. Broad spectrum vs. gram + and gram –
bacteria. Probably no plasmid
resistance.
3. Administered PO, IV, IM, or SC
4. Metabolized in the liver, excreted by the
kidneys
Review

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Fluoroquinolones
5. a. Contraindicated for patients with
hepatic or renal insufficiency
b. May cause cartilage deformities
Review