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1962 Nalidixic acid was the first quinolone discovered. Modified to enhance or limit the extent of antimicrobial activity & improve various other product attributes, such as pharmacokinetic profile, tolerability, drug interaction & toxicity of each new agent.
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Levofloxacin
Evolution of Fluoroquinolones
Addition of fluorine atom of Nalidixic acid at position 6 increased the antimicrobial potency with both gram +ve & gram -ve organisms coverage The piperazine substituent is responsible for the gram -ve activity (also anti - pseudomonal activity) of the fluroquinolones
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2nd Gen
Gram-ve Gram +ve (Except S. pneumoniae)
3rd Gen
Gram -ve Gram +ve Gram +ve (including S. pneumoniae) Intracellular bacteria Anaerobic bacteria
4th Gen
Same as 3rd generation with extended anaerobic coverage
Moxifloxacin Nalidixic acid Norfloxacin, Lomefloxacin, Ofloxacin, Ciprofloxacin Levofloxacin, Sparfloxacin, Gatifloxacin Trovafloxacin (withdrawn due to toxicity)
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Spectrum of Activity
Levofloxacin is more active against Gram +ve & Gram -ve organisms, intracellular pathogens than earlier quinolones such as Ciprofloxacin. Has excellent activity against most commonly encountered pathogens in RTIs such as Strep. pneumoniae as well as H. influenzae, M. catarrhalis & against intracellular organisms.
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Oxazine ring
oral absorption activity against gram-ve activity against some gram-ve coverage bacilli half life half life
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DNA
Stabilize
Stabilize
(+) (-)
(-)
(-) (-)
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Pharmacokinetics Profile
Steady state attained after 3 days Cmax (g/ml) 5.09 5.7 AUC (g/ml.h) 44.7 47.5 tmax (h) 1.3 1.1 t (h) 6.33 7.6 CLR (ml/min) 125.5 116.0 Vd (L/kg) 1.2 1.35 Serum protein binding around 25-40 %
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Variable
Pharmacokinetics Profile
Offers nearly 100% bioavailability after oral administration, making it possible to administer the drug at the same dosages either orally or intravenously. Hence ideal for sequential therapy in CAP/AECB.
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Pharmacokinetics Profile
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Pharmacokinetics of Quinolones
Parameter Ciprofloxacin (I.V./Oral)
70-80
Ofloxacin (I.V./Oral)
98
Sparfloxacin
92
1.2 (250 mg) 2.4 (500 mg) 4.3 (750 mg) 5.4 (1000mg)
1.5 (200 mg) 2.4 (300 mg) 2.9 (400 mg) 14.1 (200 mg) 21.2 (300 mg) 31.4 (400 mg)
4.8 (250 mg) 11.6 (500 mg) 20.2 (750 mg) 30.8 (1000mg)
Pharmacokinetics of Quinolones
Parameter
Protein Binding (%) Major Elimination Route Half-life (hours) Effect of food on absorption
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MIC breakpoints
Breakpoints as per National Committee for Clinical Laboratory Standards (NCCLS)
Strep. pneumoniae S. pyogenes Staph. aureus (methicillin-resistant) S. epidermidis Enterococcus faecalis E. faecium
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60 to 90 mins
Renal Not used in poor impairment renal function Renal impairment Renal Phototoxicity, impairment headache 3 44 %, abdominal pain 11 % nausea 5.6%
Warfarin
Oral Oral
Warfarin, Cyclosporine
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Ofloxacin
5 to 8 hrs
Ciprofloxacin
3 to 5.4 hours
Oral / IV
Renal Nausea, Warfarin, imparment vomiting, theophylline, abdominal pain caffeine, cyclosporine, glyburide
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Sparfloxacin
21 hrs
Because compared with other fluoroquinolones, Levofloxacin has a low frequency of mutation as it inhibits both DNA-gyrase & Topoisomerase IV
Hence, bacteria will have to do double mutation to show resistance
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Dosage
Indication
Acute sinusitis
Duration of treatment
10-14 days 7-10 days 5 days 7-14 days/ 5 days
7-10 days
28 days 7 days Single dose
Impaired renal clearance (creatinine clearance < 3 L / h or <50 ml /min ) Dosage adjustment is needed
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Dosage (Contd.)
Dosage in Normal Renal Function:
Indication
Bone related Infections Meningitis Opportunistic Infections (Pseudomonas aeruginosa) Bacterial Diarrhoea
Duration of treatment
4weeks or more Titrated to symptoms as per need 5 days
14 days
5 days Till Negative SputumCulture
Impaired renal clearance (creatinine clearance < 3 L / h or <50 ml /min ) Dosage adjustment is Sales Training needed
88.3
92
AMC = Amoxicillin / Clavulanic acid ; LVFX = Levofloxacin; CLR = Drugs 1998, 56 (3) pg 487-515 Clarithromycin Sales Training
LVFX = Levofloxacin; CXM = Cefuroxime; CRO = Ceftriaxone; PO = Drugs 1998, 56 (3) pg 487-515 Oral Sales Training
Comparative studies LVFX 500 od CXM 250 bid LVFX 500 od CEC 250 tid
94.6 92.6 92 92
97 95 94 87
Comparative studies
LVFX 250 od CIP 250 bid
Comparative studies
LVFX 500 od CIP 500 bid LVFX 500 od CIP 500 tid
Clinical Trials
Pharmacodynamics & Pharmacokinetics : Pharmacodynamic analysis of the activity of Levofloxacin against Streptococcus pneumoniae revealed that, 99% of the time, actual hospitalized patients achieve an AUC / MIC of > 30. This indicates that Levofloxacin will be very effective in treating S. pneumoniae infections in majority of patients. (AUC/MIC of greater than 30 required for effective eradication of bacterial & good clinical outcome).
Chemotherapy 2000; 4(suppl 1):6-14
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Lomefloxacin.
Bacterial eradication : Levofloxacin Ciprofloxacin Lomefloxacin Clinical cure : Levofloxacin Ciprofloxacin Lomefloxacin Adverse effects : Levofloxacin Ciprofloxacin Lomefloxacin 95% 94% 95% 92% 88% 80% 2% 8% 5%
The once-daily oral administration, has proven efficacy & good tolerability making Levofloxacin an excellent choice for empiric treatment of acute pyelonephritis. UTOLOGY : 1998, 52, p. 51-55 Sales Training
Comments
Levofloxacin eradication rates: 100% H. influenzae (n = 30) 100% S. pneumoniae (n = 30) 100% Staphylococcus aureus (n=10) 88% H. parainfluenzae (n = 8) 100% M. catarrhalis (n = 7) 100% Klebsiella pneumoniae (n = 3) Levofloxacin eradication rates: 100% S. pneumoniae (n = 22) 100% H. influenzae (n = 18) 100% S. aureus (n = 3)
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100
Levofloxacin200 mg bid po
%
Bacterial Cure NA Comments 2.1% relapse at late follow-up 3.8% relapse at late follow-up
NA
95
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Salient Features
Nearly 100% bioavailability making it equivalent to IV administration & for sequential use in CAP.
Effective as monotherapy in serious CAP when
Salient Features
Broad spectrum of activity covering gram +ve,
gram-ve, intracellular pathogens & anaerobic bacteria. Extended activity against respiratory pathogens such as Strep. pneumoniae, H. influenzae, M.
Salient Features
2-4 times greater antibacterial activity than
Ofloxacin with fewer side effects Increased sensitivity to DNA gyrase compared to other quinolone (Ciprofloxacin) hence better activity against gram +ve & gram-ve organisms.
Salient Features
Penetrates into neutrophils but does not interfere with its chemotaxis in vitro at concentrations upto 100 g/ml No significant changes in resistant pattern so far
Salient Features
Widely distributed in various tissues & fluids including inflammatory exudates. First quinolone to be approved for the treatment of acute sinusitis.
Salient Features
Incidence of seizures, tendinitis, pseudomembranous colitis, hemolytic episodes &
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Achieves double the AUC than twice daily dose of Ciprofloxacin Urinary excretion is 87 % as unchanged drug ,unlike with Ciprofloxacin it is only 25-35% Clinical success rates in complicated UTI : 92 % v/s 79 % Achieves 5 fold concentration in prostatic tissue than Ciprofloxacin, hence dosage is 500mg OD for 28 days v/s 500 mg BID for 28 days Convenience of OD dosage unlike Ciprofloxacin is BID Was associated with significantly greater pathogen susceptibility than Ciprofloxacin i.e. 94.7 % v/s 90.6 %
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