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 ½ 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 cetirizineLevocetirizine instead of cetirizine

– to enhance efficacy• Levofloxacin from ofloxacinLevofloxacin 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 infectionsBy Mario Furlanut et al, Journal of Antimicrobial Chemotherapy (2003) 51, 101–106.

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, 503–506.

Levofloxacin

In UTI

Levofloxacin = higher urine levels

Levofloxacin demonstrated rapid bactericidal activity against E coli in the urine (with MICs ≤32 µg/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.

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

Levofloxacin Ticarcillin /Amoxy-

claevulanicacid

Microbiological eradication rate

Microbiologicaleradication rate

7879808182838485

Levofloxacin Ticarcillin /Amoxy-

claevulanicacid

Clinical therapeutic success rate

Clinicaltherapeuticsuccess rate

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. Rimmelé 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 pneumococciby 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 β-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. aureus5. 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

Levoz

Lower MICsLower MICsLower MICsLower MICs

Guideline recommended Guideline recommended antibacterialantibacterial

Guideline recommended Guideline recommended antibacterialantibacterial

One a day antibacterial One a day antibacterial for a wide variety of for a wide variety of

indicationsindications

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 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

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

Excellent success in Excellent success in resistant typhoidresistant typhoid

Sequential therapy / Sequential therapy / combination therapycombination therapySequential therapy / Sequential therapy / combination therapycombination therapy

Excellent Excellent tolerabilitytolerability

Excellent Excellent tolerabilitytolerability