Glevo 500 3f3p5c

GLEVO

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Spectrum of activity of 4 generations of Quinolones

1st Generation

2nd Generation

3rd Generation

4th Generation

Gram -ve

Gram-ve Gram +ve (Except S. pneumoniae)

Same as 3rd generation with extended anaerobic coverage

Nalidixic acid

Norfloxacin, Lomefloxacin, Ofloxacin, Ciprofloxacin

Gram -ve Gram +ve Gram +ve (including S. pneumoniae) Intracellular bacteria Anaerobic bacteria Levofloxacin, Sparfloxacin

Trovafloxacin (withdrawn due to toxicity) 2

LEVOFLOXACIN

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Unique Chemical Structure (Levofloxacin)  A fluoroquinolone - optically active Levo - isomer of Ofloxacin

with

side effects.

 It has 2-4 times

> activity than Ofloxacin.

 Antibacterial activity is due to L - isomer (Levofloxacin) that

has > affinity for the target molecule DNA gyrase & has 128 times affinity than the D-isomer.

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Spectrum of Activity Gram-positive –Newer FQs like Levofloxacin have enhanced potency against Gram positive aerobes

• Methicillin-susceptible Staphylococcus aureus • Streptococcus pneumoniae (including PRSP) • Group and viridans streptococci – limited activity • Enterococcus sp. – limited activity

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Spectrum of Activity Gram-Negative –FQs have activity in following order(cipro=levo>gati>moxi)

• Enterobacteriaceae – including E. coli, Klebsiella sp, Enterobacter sp, Proteus sp, Salmonella, Shigella, Serratia marcescens, etc. • H. influenzae, M. catarrhalis, Neisseria sp.

• Pseudomonas aeruginosa – significant resistance has emerged; ciprofloxacin and levofloxacin with best activity 6

Spectrum of Activity Anaerobes – only trovafloxacin has adequate activity against Bacteroides sp. Some activity demonstrated also for Levofloxacin Atypical Bacteria – all FQs have excellent activity against atypical bacteria (Intracellular organisms) including: • • • •

Legionella pneumophila - DOC Chlamydia sp. Mycoplasma sp. Ureaplasma urealyticum

Other Bacteria – Mycobacterium tuberculosis, Bacillus anthracis

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Spectrum of Activity 

Broad spectrum activity against gram-positive, gram-negative and atypical bacteria



Active against both penicillin-susceptible and penicillin resistant Streptococcus (prevalence of S.pneumoniae resistant to Levofloxacin is <1%)



Efficacy established in treatment of infection of respiratory tract, genitourinary tract, skin and skin structure.

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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 RTI’s such as Strep. Pneumoniae as well as H. influenzae, M. catarrhalis & against intracellular organisms. 9

Levofloxacin-Mechanism of Action  Bacterial topoisomerases  “Packaging” of DNA to make it fit  “Unpackaging” DNA during replication 

Bind to topoisomerases  DNA breakage  death



Bactericidal activity



Concentration-

dependent killing 

Significant

postantibiotic effect

Cmax:MIC MIC

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Inhibits DNA gyrase to exert bactericidal effects

 Broad spectrum antibacterial with bactericidal activity  Binds & inhibits bacterial DNA-gyrase.

This enzyme (a type II topoisomerase) produces negative super-coiling of cellular DNA, needed for bacterial DNA synthesis.  This prevents DNA replication & results in bacterial cell death

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Pharmacokinetics Profile  Offers nearly 100% bioavailability after oral

istration, making it possible to ister the drug at the same dosages either orally or intravenously. Hence ideal for sequential therapy in CAP.

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Levofloxacin Patterns of antimicrobial activity

 Levofloxacin

exerts Concentration-dependent killing and prolonged persistent effects noticed at higher ratio of→ AUC/MIC or Peak/MIC ratio

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Achieves steady state plasma level that exceed MIC values for key pathogens for 24 hours

 Achieves plasma levels that are above (MIC) values for 24 hours

for most of the common pathogens after a single 500 mg oral or intravenous dose.  Clinical & microbiological outcomes can be predicted by the site

of infection & ratio of Cmax to MIC.  313 patients with respiratory, skin or UTI treated showed the

median Cmax to MIC ratio of 12.1  Clinical cure or improvement was seen in 99% of patients with

Cmax : ratio of > 12.2 14

Minimal Metabolism & Excretion

 Renal excretion is primary responsible for elimination of

Levofloxacin. Following oral istration, 80 to 86% of the dose was recovered in urine as unchanged drug within 24 hours & 2% recovered unchanged in faeces.

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Dosage

Dosage in normal renal function: Indication Acute sinusitis

Daily dose regimen 500mg once daily

Duration of treatment 10-14 days

Acute exacerbation of Chronic bronchitis

250 to 500mg once daily

7-10 days

CAP

500mg once daily

7-14 days

Complicated urinary tract infections including Pyelonephritis

250 mg once daily

7-10 days

Skin & soft tissue infection

500 mg once daily

7 days

Impaired renal clearance (creatinine clearance < 3 L / h or <50 ml /min ) Dosage adjustment is needed 16

Clinical studies

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Acute Maxillary Sinusitis

Dosage (mg) Comparative studies LVFX 500 od AMC 500/125 tid LVFX 500 od CLR 500 bid Non-Comparative studies LVFX 500 od

Clinical success rate (%)

Bacteriological eradication rate (%)

88.4 87.3 96.0 93.3

NA NA NA NA

88.3

92

AMC = Amoxicillin / Clavulanic acid ; LVFX = Levofloxacin; CLR = Clarithromycin Drugs 1998, 56 (3) pg 487-515 18

Community Acquired Pneumonia

Dosage (mg) Comparative studies LVFX 500 od CXM 500 bid LVFX 500 od CRO 4000 od IV Non-Comparative studies LVFX 500 od IV or PO

Clinical success rate (%)

Bacteriological eradication rate (%)

96 90

NA NA

87 86

87 87

94.7

95.1

LVFX = Levofloxacin; CXM = Cefuroxime; CRO = Ceftriaxone; PO = Oral Drugs 1998, 56 (3) pg 487-515 19

Acute exacerbation of Chronic Bronchitis

Dosage (mg) Comparative studies LVFX 500 od CXM 250 bid LVFX 500 od CEC 250 tid

Clinical success rate (%)

Bacteriological eradication rate (%)

94.6 92.6

97 95

92 92

94 87

LVFX = Levofloxacin; CXM = Cefuroxime; CEC = Cefaclor Drugs 1998, 56 (3) pg 487-515 20

Urinary tract infection

Dosage (mg)

Clinical success rate (%)

Comparative studies LVFX 250 od CIP 250 bid

92 88

Bacteriological eradication rate (%) 93.6 97.5

LVFX = Levofloxacin; CIP = Ciprofloxacin Drugs 1998, 56 (3) pg 487-515

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Skin & Soft tissue infection

Dosage (mg)

Clinical success rate (%)

Bacteriological eradication rate (%)

Comparative studies LVFX 500 od CIP 500 bid

97.8 94.3

97.5 88.8

LVFX 500 od CIP 500 tid

96.1 93.5

93.2 91.7

LVFX = Levofloxacin; CIP = Ciprofloxacin Drugs 1998, 56 (3) pg 487-515 22

Comparative Clinical Trials Aim : To compare efficacy and safety of oral Levofloxacin (500 od) versus Ciprofloxacin (500 mg bid) in the treatment of skin and skin structure infections. Success rate : Bacterial eradication :

Levofloxacin

- 96.1%

Ciprofloxacin

- 93.5%

Levofloxacin

- 93.2%

Ciprofloxacin

- 91.7%

Findings the efficacy of oral Levofloxacin for uncomplicated skin & skin structure infections due to S. aureus & S. pyogenes. (Int J Clin Pract 1998; 52(2): 69-74) IJ, March 1998 Vol. 52 No. 2 23

Salient Features  Nearly 100% bioavailability making it equivalent to IV

istration & for sequential use in CAP.  Effective as monotherapy is serious CAP when compared

with standard regimens  High tissue penetration

 Lower t½ making it OD dosage  Fewer side effects compared to 1st & 2nd generation

quinolones 24

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. catarrhalis & intracellular pathogens

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Salient Features

 2-4 times greater antibacterial activity that Ofloxacin

with fewer side effects  Increased sensitivity to DNA gyrase compared to

other quinolone (Ciprofloxacin) hence better activity against gram +ve & gram-ve organisms.  MIC equals bactericidal concentrations. 26

Salient Features

 Penetrates into neutrophils but does not interfere with its

chemotaxis in vitro at concentrations upto 100 µg/ml  No significant changes in resistant pattern so far reported

because it has low frequency for mutations  Negligibly metabolised by the liver & mainly excreted

unchanged in urine.  Bioavailability is not affected by food 27

Salient Features

 Widely distributed in various tissues & fluids including

inflammatory exudates.  First quinolone to be approved for the treatment of

acute sinusitis.  Phototoxicity is infrequent & is <1% while it is 8% with

Sparfloxacin.

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Salient Features  Incidence of seizures, tendinitis, pseudomembranous

colitis, hemolytic episodes & arrhythmias is rare to none.  Interactions with theophylline, NSAIDs,

antihyperglycaemic drugs, Digoxin, Calcium carbonate, Probenecid Cyclosporin are clinically

insignificant & does not need dose adjustment.

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