Levofloxacin

1. Levofloxacin

2. Background
•Ofloxacin is a fluoroquinolone composed of 2
isomers, known as levo and dextro isomers.
•Levofloxacin is the isolated optically active levo
isomer of ofloxacin.
•Pharmacokinetic properties of levofloxacin
permit
●
Dosing once daily, as opposed to ofloxacin, which
is given twice a day.
●
Efficacy, which is superior to commonly used
fluoroquinolones like ofloxacin or ciprofloxacin.

3. Racemic mixtures
•Many commonly used drugs are 50:50 mixtures
of 2 stereoisomers of the drug molecule and
are hence called as a racemic mixture or
racemate.
•The 2 stereoisomers (enantiomers) are
identical in chemically, but structurally are
mirror images of each other
●
‘Left-handed’ (‘levo’ or ‘s-’) form
●
Designated as levorotatory, L-,l-, or (-) because
molecules rotate plane polarized light to the left
●
‘right-handed (‘dextro’ or ‘r-’) form
●
Designated as dextrorotatory, D-,d-, or (+) because
molecules rotate plane polarized light to the right

4. Chirality
•The study of these 2 mirror images of the
substance as enantiomers or stereoisomers is
chirality
•This can have significance on drug action e.g.
interaction with receptors. Analogy is like
placing a hand in a glove.
●
the ‘left handed’ drug will only fit the
‘left-handed’ receptor and vice versa.
●
So, within a racemic mixture, only ½ of
the molecules are responsible for effect.

5. Advantages of chirality
•Potential advantages of chiral seperation:
1.Increased potency & selectivity and fewer
unwanted effects
2.Improved onset & duration of effect
3.Decreased risk for drug interactions
•Replacement of an approved racemate
mixture by a single isomer is also used
●
to decrease side effects
●
Levocetirizine instead of cetirizineLevocetirizine instead of cetirizine
●
to enhance efficacy
●
Levofloxacin from ofloxacinLevofloxacin from ofloxacin

6. Levofloxacin
Viewing the
Benefits
&
Add-vantages

7. Mechanism of action
•Bactericidal against susceptible organisms.
–It interferes with bacterial DNA synthesis by
inhibiting 2 important bacterial enzymes:
1.Topoisomerase II,
– Topoisomerase II (DNA gyrase) is responsible for relaxing
supercoiled DNA during normal transcription.
2.Topoisomerase IV.
–Topoisomerase IV interferes with separation of chromosomal
DNA during cell division.

8. Absorption
•Rapidly and completely absorbed on oral
administration.
•Absolute bioavailability [500 mg dose] is 99%.
•When administered with food -
–Slight decrease in peak plasma concentration (Cpmax) & time
to peak serum concentration (tmax);
–Therefore, can be administered without regard to food.
•Linear pharmacokinetic profile -
–Peak plasma concentrations achieved within 1-2 hours after
oral dosing.

9. Distribution
•Large volume of distribution with adequate
concentrations to eliminate a majority of
pathogens that cause common infections–
–Into many tissues & body fluids, including lungs / blister fluid.
–Penetration into inflammatory exudate also.
•With equal dosing of oral levofloxacin and IV
levofloxacin (mg per mg), the area under the
serum concentration-time curve (AUC) is
comparable;
–Therefore, the oral & IV routes are interchangeable.

10. Sequential therapy IV Vs. Oral
Pharmacokinetic aspects of
levofloxacin 500 mg once
daily during sequential
intravenous/oral therapy in
patients with lower
respiratory tract infections
By Mario Furlanut et al,
Journal of Antimicrobial
Chemotherapy (2003) 51,
101–106.

11. Studies with levofloxacin

12. Levofloxacin
In RTI

13. Coverage of Main RTI Pathogens
•By Levofloxacin

14. Coverage of Main RTI Pathogens
•By Levofloxacin

15. Comparison

16. Comparative therapy in RTI
•One comparative study in RTI proved
–Levofloxacin at 500 mg./ 750 mg. > more effective
than ciprofloxacin 500 mg.
–750 mg levofloxacin generated more favourable
bacterial killing > 500 mg levofloxacin regimen.
–In addition to using the 750 mg levofloxacin dose
for nosocomial infections, this dose may also prove
useful for the management of resistant
pneumococcal infections.
Comparative antimicrobial activity of levofloxacin and ciprofloxacin against
Streptococcus pneumoniae by Mark W. Garrison et al, Journal of Antimicrobial
Chemotherapy (2003) 52, 503–506.

17. Levofloxacin
In UTI

18. Levofloxacin = higher urine levels
Levofloxacin
demonstrated
rapid
bactericidal
activity
against E coli
in the urine
(with MICs ≤32
µg/mL at 1.5
hr).

19. Lesser resistance with just 5 days
of therapy

20. Significantly lower resistance rates
•More isolates susceptible to Levofloxacin than
to ciprofloxacin.
–24 out of 68 isolates that were susceptible to
Levofloxacin were fully or partially resistant to
ciprofloxacin;
–0 isolates out of 596 that were susceptible to
ciprofloxacin were resistant to Levofloxacin.
•The study also showed:
–50.1% of gram-ve pathogens = fully resistant to ampicillin
–22.1% of gram-ve pathogens = fully resistant to TMP/SMX

21. Significantly high success in prostatitis
•Various studies for chronic bacterial prostatitis
have shown that mean duration of drug
administration = 40 days.
•Clinical cure at 8 weeks = 88.9%
•Bacteriological eradication rate = 79.2%
•The take home message –
–Minimum duration of therapy is 6-8 weeks
–Significant decrease in PSA after treatment with
levofloxacin.

22. Levofloxacin
In SSTI

23. Activity in complicated SSTI
•One study compared levofloxacin & Ticarcillin /
Amoxy-claevulanic acid regimens in
complicated SSTIs.
Once-Daily, High-Dose Levofloxacin versus Ticarcillin-Clavulanate alone or followed by
Amoxicillin-Clavulanate for complicated Skin and Skin-Structure Infections: A
Randomized, Open-Label Trial by Donald R. Graham et al, Clinical Infectious Diseases
2002;35:381–389
65
70
75
80
85
LevofloxacinTicarcillin /
Amoxy-
claevulanic
acid
Microbiological eradication rate
Microbiological
eradication rate
78
79
80
81
82
83
84
85
LevofloxacinTicarcillin /
Amoxy-
claevulanic
acid
Clinical therapeutic success rate
Clinical
therapeutic
success rate

24. Activity in diabetic foot infections
•Studies have shown showed good tissue
penetration of levofloxacin in diabetic foot
ulcers.
•In combination with adequate surgical
debridement, levofloxacin seems well suited to
the treatment of skin structure infections of
diabetics caused by susceptible organisms.
Tissue and serum levofloxacin concentrations in diabetic foot infection patients by K.
Oberdorfer et al, Journal of Antimicrobial Chemotherapy (2004) 54, 836-839.

25. Activity in bone
•The degree of penetration of an antibiotic into
the infected site is an important determinant of
therapeutic success.
•Levofloxacin is widely used in the treatment of
serious bone and synovial tissue infections as
the concentrations of levofloxacin achieved in
cancellous and cortical bone tissue and in
synovial tissue are greater than the breakpoint
for susceptible organisms, which is ≤2 mg/L.
Diffusion of levofloxacin into bone and synovial tissues by T. Rimmelé et al, Journal of
Antimicrobial Chemotherapy (2004) 53, 533-535.

26. Levofloxacin
In combination

27. Better activity in combination
•Studies have shown
that ceftriaxone acts
synergistically with
levofloxacin in
experimental
meningitis and
reduces
levofloxacin-induced
resistance in
penicillin-resistant
pneumococci
by L. Flatz et al,
Journal of
Antimicrobial
Chemotherapy (2004)
53, 305-310

28. Better activity in combination
•Why is this
activity seen?
•This is because
combination
antibiotic therapy
prevents
selection of
multidrug
resistance due to
overproduction
of efflux pump
system along
with β-lactamase
overproduction.

29. Levofloxacin
In Typhoid

30. Typhoid and levofloxacin
•Resistance / intolerance to oral ciprofloxacin
may be present with subsequent clinical failure
of typhoid fever treatment.

31. Typhoid and levofloxacin
•GI intolerance to oral ciprofloxacin may be
present with possible hepatic adverse reactions
leading to failure of therapy.

32. Levofloxacin
In Usage

33. Guidelines, and Recommendations
•AAO guidelines
–for acute bacterial sinusitis
•For initial treatment failures
•For adults with prior antibiotic exposure in the previous 4 to 6 weeks
•Stanford Guide
–for ABS and CAP in patients with
•Previous antibiotic therapy
•Severe ABS who have failed 3 days of initial therapy
•As primary therapy for CAP if comorbidity is present
–recommends levofloxacin 750 mg/once daily for 5 days
•ATS/IDSA guidelines
–for community acquired pneumonia
•First-line fluoroquinolone monotherapy in CAP for patients with previous
antibiotic therapy, as well as first-line for outpatients and hospitalized patients
at increased risk for infection with specific pathogens due to risk factors such
as cardiopulmonary disease

34. Indications
1.For sinusitis
–due to S. pneumoniae, H. influenzae or M. catarrhalis.
2.For bronchitis
–due to S. aureus, S. pneumoniae, H. influenzae, H. parainfluenzae or M.
catarrhalis.
3.For severe pneumonia
–pathogens, which include the aforementioned organisms in addition to K.
pneumoniae, C. pneumoniae, L. pneumophila, or M. pneumoniae.
4.For uncomplicated / complicated skin infections
–caused by S. aureus or S. pyogenes where Levofloxacin ® superior to
ciprofloxacin in infections caused by S. aureus
5.For UTI, chronic prostatitis and pyelonephritis
–Due to E. faecalis, E. cloacae, E. coli, K. pneumoniae, Proteus mirabilis or
Pseudomonas nut not active against MRSA.
6.For typhoid
–Extremely effective against gram -ve bacteria making it an excellent antibiotic
for infections of the gastrointestinal tract

35. Side effects and ADRs
•Gastrointestinal distress,
•Skin rashes, phototoxicity,
•Headache, dizziness, insomnia,
•Tendinitis.
•Theophylline increases concentration of
ciprofloxacin but not of levofloxacin
•May be associated with QT interval
prolongation.
•Absorption ¯ with agents containing Al, Mg, Ca,
Zn, Fe.

36. Dosing
•Administration/Dosing: IV/PO
–PO: 250-750 mg daily with meals for 5/14/56 days
–IV: 250-750 mg infused over 60 minutes or 90
minutes (750mg infusion)
•Clearance/Elimination:
–mostly through the kidneys via active tubular
secretion.
•Bioavailability is the same for PO and IV
administration.

37. Summary
Levoz
Lower MICsLower MICs
Guideline recommended Guideline recommended
antibacterialantibacterial
One a day antibacterial One a day antibacterial
for a wide variety of for a wide variety of
indicationsindications
5 days therapy in URTI 5 days therapy in URTI
Higher urine levels for Higher urine levels for
better UTI activity / ↓ in better UTI activity / ↓ in
PSA in ch. prostatitisPSA in ch. prostatitis
Excellent success in Excellent success in
resistant typhoidresistant typhoid
Sequential therapy / Sequential therapy /
combination therapycombination therapy
Excellent Excellent
tolerabilitytolerability