GLEVO

Spectrum of activity of 4 generations of Quinolones

1st Generation
Gram -ve

2nd Generation
Gram-ve Gram +ve (Except S. pneumoniae)

3rd Generation
Gram -ve Gram +ve Gram +ve (including S. pneumoniae) Intracellular bacteria Anaerobic bacteria Levofloxacin, Sparfloxacin

4th Generation
Same as 3rd generation with extended anaerobic coverage

Nalidixic acid

Norfloxacin, Lomefloxacin, Ofloxacin, Ciprofloxacin

Trovafloxacin (withdrawn due to toxicity)

2

LEVOFLOXACIN

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.

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

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

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.

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.
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 ConcentrationSignificant

dependent killing

Cmax:MIC MIC

postantibiotic effect

10

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

11

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.

12

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

13

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

15

Dosage

Dosage in normal renal function:

Indication Acute sinusitis Acute exacerbation of Chronic bronchitis CAP Daily dose regimen 500mg once daily 250 to 500mg once daily 500mg once daily Duration of treatment 10-14 days 7-10 days 7-14 days

Complicated urinary tract infections including Pyelonephritis

Skin & soft tissue infection

250 mg once daily

500 mg once daily

7-10 days
7 days

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

Clinical studies

17

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 (%)

88.4 87.3 96.0 93.3

Bacteriological eradication rate (%)

NA NA NA NA

88.3

92
Drugs 1998, 56 (3) pg 487-515
18

AMC = Amoxicillin / Clavulanic acid ; LVFX = Levofloxacin; CLR = Clarithromycin

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 (%)

96 90 87 86

Bacteriological eradication rate (%)

NA NA 87 87

94.7

95.1
Drugs 1998, 56 (3) pg 487-515
19

LVFX = Levofloxacin; CXM = Cefuroxime; CRO = Ceftriaxone; PO = Oral

Acute exacerbation of Chronic Bronchitis

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

Clinical success rate (%)

94.6 92.6 92 92

Bacteriological eradication rate (%)

97 95 94 87

LVFX = Levofloxacin; CXM = Cefuroxime; CEC = Cefaclor

Drugs 1998, 56 (3) pg 487-515
20

Urinary tract infection

Dosage (mg)
Comparative studies LVFX 250 od CIP 250 bid

Clinical success rate (%)

92 88

Bacteriological eradication rate (%)

93.6 97.5

LVFX = Levofloxacin; CIP = Ciprofloxacin

Drugs 1998, 56 (3) pg 487-515

21

Skin & Soft tissue infection

Dosage (mg)
Comparative studies LVFX 500 od CIP 500 bid LVFX 500 od CIP 500 tid

Clinical success rate (%)

97.8 94.3 96.1 93.5

Bacteriological eradication rate (%)

97.5 88.8 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 Ciprofloxacin Levofloxacin Ciprofloxacin - 96.1% - 93.5% - 93.2% - 91.7%

Findings support 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)
IJCP, March 1998 Vol. 52 No. 2
23

Salient Features
Nearly 100% bioavailability making it equivalent to IV

administration & for sequential use in CAP.

Effective as monotherapy is serious CAP when compared

with standard regimens

High tissue penetration

Lower t 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

25

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 g/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.

28

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.

29