Leflocad

Levofloxacin
 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
1. Dosing once daily, as opposed to ofloxacin, which is
given twice a day.
2. Efficacy, which is superior to commonly used
fluoroquinolones like ofloxacin or ciprofloxacin.
 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
 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 of
the molecules are responsible for effect.
 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 cetirizine
to enhance efficacy
Levofloxacin from ofloxacin
Levofloxacin

Viewing the
Benefits
&
Add-vantages
 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.
 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.
 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.
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,
101106.
Studies with levofloxacin
Levofloxacin

In RTI
 Coverage of Main RTI Pathogens
By Levofloxacin
 Coverage of Main RTI Pathogens
By Levofloxacin
Comparison
 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, 503506.
Levofloxacin

In UTI
Levofloxacin = higher urine levels
Levofloxacin
demonstrated
rapid
bactericidal
activity
against E coli
in the urine
(with MICs 32
g/mL at 1.5
hr).
Lesser resistance with just 5 days
of therapy
 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
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.
Levofloxacin

In SSTI
 Activity in complicated SSTI
One study compared levofloxacin & Ticarcillin /
Amoxy-claevulanic acid regimens in
complicated SSTIs.
Clinical therapeutic success rate Microbiological eradication rate

85 85
84
83 80
82
75
81
80 Clinical Microbiological
70 eradication rate
79 therapeutic
78 success rate 65
Levofloxacin Ticarcillin / Levofloxacin Ticarcillin /
Amoxy- Amoxy-
claevulanic claevulanic
acid acid

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;35:381389
 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.
 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. Rimmel et al, Journal of
Antimicrobial Chemotherapy (2004) 53, 533-535.
Levofloxacin

In combination
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
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 -lactamase
overproduction.
Levofloxacin

In Typhoid
 Typhoid and levofloxacin
Resistance / intolerance to oral ciprofloxacin
may be present with subsequent clinical failure
of typhoid fever treatment.
 Typhoid and levofloxacin
GI intolerance to oral ciprofloxacin may be
present with possible hepatic adverse reactions
leading to failure of therapy.
Levofloxacin

In Usage
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
 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
 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.
 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.
 Summary
Lower
LowerMICs
MICs

Excellent
Excellent Guideline
Guidelinerecommended
recommended
tolerability
tolerability antibacterial
antibacterial

One
Oneaadaydayantibacterial
antibacterial
Sequential
Sequentialtherapy
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