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QUINOLONES - Coggle Diagram
QUINOLONES
FLUOROQUINOLONES
MOA
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- Inhibit bacteria DNA gyrase ( topoisomerase II)
- This prevents relaxation of positively supercoiled DNA for normal transcription & replication
- Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into respective daughter cells
- Mammalian topoisomerase II has low affinity for FQs→ hence safe.
RESISTANCE
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Mechanisms
- One or more point mutations in the quinolone binding region of target enzyme → ↓ affinity to FQs
- Change in permeability of organism
- 2 types of plasmid mediated resistance have been described
◘ Utilised Qnr proteins→ protect DNA gyrase from FQs
◘ Variant of aminoglycoside acetyltransferase capable of modifying ciprofloxacin
- Resistance to one FQ→ cross resistance to all other members
CIPROFLOXACIN Prototype
SPECTRUM :check: Highly susceptible
- E.coli
- N. gonorrheae
- K. pneumoniae
- N. meningitidis
- Enterobacter
- H. influenzae
- Salmonella typhi
- Nontyphoid salmonella
- Shigella
- Proteus
- H. ducreyi
- Campylobacter jejuni
- Yersinia enterocolitica
- Vibrio cholerae
SPECTRUM :check: Moderately susceptible
- Pseudomonas aeruginosa
- Brucella
- Listeria
- Staph. epidermidis
- Brahmanella catarrhalis
- Legionella
- Mycoplasma
- Chlamydia pneumophila
- Bacillus anthracis
- Myco. tuberculosis
Low/Variable susceptibility
- Strep. pyogenes, Strep. faecalis, Strep. pneumoniae, MRSA, Myco. kansasii, Myco. avium
- Most potent 1st Gen FQ
- Active against a broad range of bacteria
○ esp. aerobic G-ve bacilli→ enterobacteriacease, neisseria
○ MIC <0.1μg/ml- against these bacteria
○ G+ inhibited at relatively higher conc.
Distinctive Microbiological Features of FQs :check:
- Bactericidal activity & high potency
○ MBCs close to MICs
- Relatively long post-antibiotic effect on Enterobacteriacease, pseudomonas & staph
.
- Low frequency of mutational resistance
- Low propensity to select plasmid type resistant mutants*
- Protective intestinal stretococci & anaerobes spared
- Less active in acidic pH
PHARMACOKINETICS
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- Rapid oral abs.
- Food delays abs.
- FPM occurs
- Oral abs. impaired by divalent/trivalent cations in antacids
- Attain bactericidal conc. in blood
○ Ciprofloxacin & other FQs except norfloxacin
- Good tissue penetrability
- Conc. in lung/sputum/ muscle/ prostate/ phagocytes exceeds that of plasma
- But CSF & aqueous levels are lower
- Excr. in urine, both by GF & TS
- Urinary& biliary conc. 10-50x higher than plasma
- Dosage adjustment
○ Patients with creatinine clearance <50ml/min
ADVERSE EFFECTS :warning:
- Good safety record
- S/E ~10% patients-generally mild
GI S/E
- Nausea, vomiting
- Bad taste, anorexia
CNS
- Dizziness/ headache
- Restlessness/ anxiety
- Insomnia/ impairment of conc.
- Rare: tremors/ seizures
Skin/HS
- Rash/ pruritis
- Photosensitivity/ urticaria
- Swelling of lips,etc
Tendonitis & tendon rupture
- Patients >60yrs
- Patients receiving corticosteroids
:warning:
- Cautious use in children
- C/I in pregnancy
INTERACTIONS :forbidden:
- ↑ Theophylline, caffeine & warfarin conc. d/t inhibiton of metabolism
○ CNS toxicity d/t concurrent use of theophylline + FQ
- NSAIDs enhance CNS toxicity of FQs
- Antacids, sucralfate & iron salts given together ↓ FQ abs.
USES :check: 1. UTI
- High cure rates, even in complicated cases
2. Gonorrhea
3.Chancroid
- Ciprofloxacin 500mg BD x3days: 2nd line to ceftriaxone/azithromycin
4. Bacterial gastroenteritis
- MC used for empirical therapy
5. Typhoid
- If S. typhi strain is sensitive, Ciprofloxacin dose of 750mg BD for 10d as 1st line
- Or 200mg iv 12 hrly
- Bactericidal→ quick defervescence, early symptomatic relief & prevention of carrier state
- Typhoid carriers→ 750mg BD for 4-8wks
6. Bone/ soft tissue/ gynec/ wound infections
- By resistant Staph. & G-ve bacteria
- High cure in osteomyelitis & joint infections
- Prolonged trt reqired
- Used with clindamycin/metronidazole ( to cover anaerobes) for Diabetic foot
7. Resp. infections
- Atypical pneumonia d/t
○ Mycoplasma, Legionella,Branh. catarrhalis, Chlamydiae
- 2nd gen FQs→ pneumonias & c/c bronchitis
- Anthrax→DOC & Post-exp. trt. of inhalational anthrax
8. TB
- Moxifloxacin, Levofloxacin→ 2nd line components of combination chemotherapy against MDR TB
- Less active against Myco. tuberculosis but most active against MAC
9. G-ve Septicemias
- Parenteral Cipro+ 3rd gen cephalosporin/AG
10. Meningitis
- G-ve bacterial meningitis
- In immunocompromised/ those with CSF shunts
- Cure meningococcal carrier state
11. Prophylaxis
- Neutropenic cancer/ other susceptible
12. Conjunctivitis
- G-ve bacteria-topical therapy
FIRST GEN FQs
NORFLOXACIN
- Least potent FQ
- MIC values for most G-ve bacteria are
2-8x > ciprofloxacin
- Many pseudomonas & other G+ bacteria not inhibited
- Does not achieve adequate systemic conc.
- Use:
UTIs (C/c→ 8-12 wks)
Bacterial diarrheas→ high conc. in gut, anaerobic flora not disturbed
PEFLOXACIN
- Methyl derivative of norfloxacin
- More lipid soluble
- Complete oral abs.
- Attains ↑ plasma conc., penetrates tissues
- Cross BBB→ used for menigeal inf.
- Highly metabolised
○ Partly to norfloxacin→ contributes to activity
- Longer T½
○ Cumulates on repeated dosing
○ Hence eff. in some systemic infections as well
- Dose of pefloxacin
○ ↓ in liver disease
○ Not changed in renal insuff.
OFLOXACIN
- Less potent than CF against G-ve
- Equally potent against Strep. pyogenes & G+ cocci & certain anerobes
- Activity against chlamydia, mycoplasma
○ Alt drug for nonspecific urethritis, cervicitis, atypical pneumonia
- Inhibits M. tuberculosis
○ Used in resistant TB
- High activity against Myco. leprae
○ Use in alt. multidrug therapy regimen
PK :check:
- Relatively lipid soluble
- Oral BA high
- Higher plasma conc. attained
- Food does not interfere with abs.
- Excreted largely unchanged in urine
○ Dose ↓ in renal failure
- Comparable to CF in therapy of systemic & mixed inf.
- Suitable for c/c bronchitis/ other resp./ENT inf. & chlamydia urethritis as alt. drug
- Less inhibiton of theophylline metabolism
SECOND GEN FQs
LEVOFLOXACIN
- Active levo(S) isomer of Ofloxacin
- Improved action against- Strep. pneumoniae, M. tuberculosis, some G+ & G-ve bacteria
- Anaerobes moderately susceptible
- Oral BA ~100%
- Excr. unchanged
- Single dose sufficient→ slower elmn. & higher potency
- PK of theophylline, warfarin, cyclosporine & zidovudine → remain unchanged
Use
- CAP , exacerbations in C/c bronchitis
- SInusitis, pyelonephritis, prostatitis, UTI
- Skin/ soft tissue infections
- Alt. drug for chlamydial urethritis
- 2nd most active FQ for TB
○ In india, component of standardized regimen for MDR-TB
LOMEFLOXACIN
- 2nd Gen difluorinated quinolone
- More active against some G-ve bacteria & chlamydia
- D/t phototoxicity & QT prolongation, withdrawn in several countries
SPARFLOXACIN
- 2nd gen, difluorinated
- Enhanced activity against G+ bacteria, bacteroides, other anaerobes, mycobacteria
Use
- Pneumonia
- Exacerbations of c/c bronchitis, sinusitis, ENT infections
Adverse effects
- Phototoxic reactions
- Prolonged QTc interval
- Fatal arrhythmias
MOXIFLOXACIN
- Long acting 2nd gen FQ
- High activity against Strep. pneumoniae, other G+ bacteria including ß lactam/macrolide resistant ones & some anaerobes
- Most potent FQ against M.tuberculosis
○ Extensively used in MDR-TB
- Bacterial topoisomerase IV is main target of action
- Used for pneumonias, bronchitis, sinusitis, otitis media
- Urinary conc. low→ not used for UTIs
○ No dose adj. in renal disease
- Metabolised in liver
○ Not given to liver disease patients
Adverse effects
- Similar to other FQs
- Prolong QTc interval
○ Not given to patients predisposed to seizures & those receiving proarrhythmic drugs
- Rarely phototoxicity
GEMIFLOXACIN
- Broad spectrum FQ
- Active against:
○ Aerobic G+ bacteria : Strep. pneumoniae, H. influenza, Moraxella, Mycoplasma pneumoniae, Chlamydia pneumophila, Klebsiella & some MDR strains
○ Some anaerobes also inhibited
- Rapid abs.
- Limited metabolism
- Excr. in urine & feces
- Dose is halved→ if creatinine clearance <40ml/min
ADR
- Diarrhea, nausea, headache, dizziness, rise in serum aminotransferases
- Skin rashes common
- Enhance warfarin effect
- Risk of additive QTc prolongation with other drugs
Use
- Indicated in CAP & exacerbations of c/c bronchitis
PRULIFLOXACIN
- Newer 2nd gen FQ
- Prodrug of Ulifloxacin
- Ulifloxacin:
○ Broad spectrum
○ Active against both G+ & G-ve, including many resistant strains
- Rapid abs→ FPM→ Ulifloxacin
- Excr. unchanged in urine
Use
- A/c exacerbations of c/c bronchitis
- Uncomplicated/ complicated UTI
ADR
- GI, CNS disturbances
- Urticaria, photosensitivity
- No QTc prolongation
PAZUFLOXACIN
- Atypical quinolone with a fused tricyclic ring
- Inj. formulation→ mesylate
Spectrum
- Broad spectrum
- G+, G-ve, several resistant strains, some anaerobes
- Enterobacteriaceae
- Resitant Pseudomonas, MRSA, ampicillin resistant H.influenzae, K.pneumoniae
- Inhibits both DNA gyrase & topoisomerase IV
- Penetrates most body fluids & CSF
- Excr. in urine unchanged
Use
- Pneumonia, lung abscess
- upper/lower UTI
- Peritonitis, intraabdominal abscess, endometritis
- Secondary burns infections, nosocomial infections.
ADR
- Nausea, diarrhea, rashes, rarely seizures
BALOFLOXACIN
+ Bactericidal against G+ & G-ve, including Strep. pneumoniae & MRSA
- Inhibit bacterial DNA gyrase
- Well absorbed orally, little metabolism→ excr. in urine
- Only limited data on safety & efficacy known
- Synthetic antimicrobials having quinolone structure
- Active primiarily against G-ve bacteria
- 1st member→ Nalidixic acid
- Fluoroquinolones→
○ fluorination at position 6 & introduction of piperazine substitution at position 7
NALIDIXIC ACID
SPECTRUM :check:
- Gram -ve bacteria
+ E coli, Proteus, Klebsiella, Enterobacter, Shigella
- Resistance develops rapidly
-
PHARMACOKINETICS :check:
- Abs. oral
- High PPB
- Partly metabolised in liver
- One of the metabolites is active
- Excr. in urine
- T½~8hrs
USES :check:
- Plasma conc. of free drug is non-therapeutic for systemic infections
- High conc. in urine & gut lumen is lethal to common urinary pathogens & diarrhea causing coliforms
ADVERSE EFFECTS :warning:
- Neurotoxicity
○ headache, drowsiness
○ vertigo, visual disturbances
○ occassionally seizures
- Individuals with G6PD deficiency→ hemolysis
- C/I in infants