Introduction

Levofloxacin is a synthetic broad spectrum antibacterial agent for oral and intravenous administration. Levofloxacin is a pure(s)-enatiomer of the racemic drug. Levofloxacin achieves the highest C max among all the quinolones which is not achieved by any quinolone in any dose or dosage form. Levofloxacin is bactericidal to a wide range of bacteria including many Gram-positive, Gram-negative, atypical and anaerobic organisms.

Levofloxacin in the dose of 250 mg orally o.d. has been a very effective, first choice drug in various urinary tract infections.

Levofloxacin in the dose of 500 mg orally once daily has been very effective in the treatment of AECB, community acquired pneumonia, acute maxillary sinusitis, skin and skin structure infections.

Increasing the dose of Levofloxacin to 750 mg exploits the pharmacokinetic advantages, by increasing peak drug concentrations.

According to a study published in Clinical Infections and Dis 2003; 37: 752-763, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and the atypical Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae have been listed as the more important pathogens in pneumonia. There is a trend toward drug-resistance, particularly documented for S. pneumoniae , with 18.4% penicillin resistance reported in one study.

It is a known fact that the quinolones have a concentration dependant killing. More the concentration (C max ) better is the killing effect. Increasing the dose of levofloxacin, increases the C max of levofloxacin further and gives even higher bactericidal effect .

Recent reports indicate enhanced bactericidal activity of levofloxacin 750 mg in comparison to levofloxacin 500 mg. Thus, levofloxacin 750 mg is very important for resistant organisms, organisms causing nosocomial pneumonia and skin and skin structure infections.

A higher dose of levofloxacin is needed for skin & skin structure infections because these infections often occur in patients with underlying conditions, such as poor circulation and compromised immune systems. The 750 mg dose provides enough concentration for such infections.

Pseudomonas infection in nosocomial pneumonia is a problem which has to be dealt with a higher concentration of the drug. Levofloxacin 750 mg achieves a very high C max which is bactericidal to all the organisms causing nosocomial infections.

Pharmacodynamics of Levofloxacin 750 mg

 

The mechanism of action of levofloxacin involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerase), enzymes required for DNA replication, transcription, repair and recombination.

With levofloxacin MBC @ MIC. Leading to greater bactericidal effect.

Levofloxacin has in vitro and in vivo activity against a wide range of Gram-negative, Gram-positive, atypical and anaerobic organisms

.Aerobic Gram-positive micro-organisms
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus saprophyticus

Streptococcus pneumoniae
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus milleri
Streptococcus viridans
Enterococcus faecalis

Aerobic Gram-negative organisms
Escherichia coli
Enterobacter spp.
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Legionella pneumophila
Moraxella catarrhalis
Proteus spp.

Pseudomonas aeruginosa
Serratia marcescens
Acinetobacter spp.
Citrobacter spp.
Morganella morganii
Providencia spp.

Atypical micro-organisms
Chlamydia pneumoniae
Mycoplasma pneumoniae
Legionella pneumophila

Anaerobic organisms
Prevotella
Peptostreptococci

Intracellular mycobacteria
Mycobacterium tuberculosis

Resistance

 

Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range : 10 -9 to 10 -10 ). Recent results from the TRUST surveillance program evaluating the resistance in levofloxacin have indicated that <1% of isolates of organisms were resistant to levofloxacin.

Pharmacokinetics of Levofloxacin 750 mg

• Levofloxacin is rapidly and completely absorbed after oral administration.
• It can be given with or without food.
• Levofloxacin has 100% oral bioavailability.
• Levofloxacin has linear pharmacokinetics.
• The ratio of peak concentration to minimum inhibitory concentration has been suggested as one of the predictive pharmacodynamic parameters for the bacteriologic and clinical responses of fluoquinolones.

So, higher the C max : MIC ratio, higher will be bactericidal effect.

• C max of Levofloxacin 750 mg is 8.6 mg/L which is much higher than the C max of levofloxacin 500 mg which is 6.2 mg/L. Hence the bactericidal effect is more in levofloxacin 750 mg.
• Another important parameter for bactericidal effect is the ratio of AUC : MIC of the quinolone. Hence higher the ratio, greater the bactericidal effect.

• AUC with levofloxacin 750 mg is 91 mg.h/L whereas with levofloxacin 500 mg it is 47.5 mg.h/L. Hence the bactericidal effect of levofloxacin 750 mg is nearby two times that of levofloxacin 500 mg.
• Levofloxacin distributes rapidly throughout the body and has a widespread distribution into body tissues.
• At steady state, mean C max and minimum plasma concentration (C min ) values in the skin were 11.77 and 2.35 mg/L in this study with respective values in plasma of 8.99 and 0.99 mg/L. These data support the use of oral levofloxacin 750 mg once daily in complicated skin and skin structure infections.
• Oral levofloxacin 750 mg shows extensive penetration in the pulmonary tissue, according to the study published in Chest, April 2001.

• Levofloxacin undergoes limited metabolism and is excreted by the kidney.
• Most of the levofloxacin is excreted unchanged in the urine.

Indications for Levofloxacin 750 mg

• Community-acquired pneumonia
• Nosocomial pneumonia
• AECB
• Complicated skin & skin structure infections.
• MDR-TB

Clinical efficacy: Levofloxacin 750 mg

 

1. Community-Acquired Pneumonia

In this multicentre, double blind investigation, subjects (528 patients) with mild to severe CAP (community-acquired pneumonia) were randomized to treatment with levofloxacin dosage of 750 mg per day for 5 days or 500 mg per day for 10 days. Clinical success rates were 92.4% in 750 mg group and 91.1% in the 500 mg group.

A 5 day course of levofloxacin 750 mg is as effective as levofloxacin 500 mg for 10 days.

Clinical Infect Dis; 2003; 37: 752-760, 761-763

2. Nosocomial Pneumonia

In patients with severe nosocomial pneumonia the bacteriological response rates with sequential levofloxacin 750 mg once daily was similar to that seen in intravenous Imipenem-Cilastatin (± switch to oral Ciprofloxacin) in a randomized non-blind trial (438 patients). The microbiological eradication rate with levofloxacin was 67% and with Imipenem-Cilastatin was 61%.

Drugs 2002; 62(14): 2127-2167

3. Complicated skin & skin structure infections

In a randomized, non-blind multicentre trial evaluating 399 patients in complicated skin and skin structure infections levofloxacin 750 mg (o.d.) was compared with ticarcillin-clavulanate 3.1 g (4 times daily). The clinical success rates were 84% with levofloxacin and 80% with ticarcillin-clavulanate combination and bacteriological cure rates were 84% and 71% respectively.

Drugs 2002; 62(14): 2127-2167

Levofloxacin 750 mg: Scientific Rationale

1. Levofloxacin 750 mg has highest C max of 8.6
   mg/L, much higher than Levoflox 500 which has 6.21.
2. AUC is nearly 2 times that of Levofloxacin
   500 mg and hence bactericidal effect is nearly 2 times greater.
3. Extensive penetration in pulmonary tissue. Concentration in epithelial lining fluid in lungs of Levofloxacin 750 mg is more than twice that of Levofloxacin 500 mg and nearly 12 times that of Ciprofloxacin 500 mg.
4. Levofloxacin 750 mg for 5 days is equivalent to Levofloxacin 500 mg for 10 days in CAP. The therapy is shortened with increased compliance and decreased costs.
5. Levofloxacin 750 mg showed 67% microbiological success rates in comparison to 61% of imipenem-cilastatin injection in nosocomial pneumonia.
6. In complicated skin & skin structure infections the clinical success and bacteriological success rates were higher than ticarcillin-clavulanate
   3.1 g given every 4-6 hours.
7. Levofloxacin 750 mg is recommended in (MDR-TB) tuberculosis by ATS and Canadian Thoracic Society.
8. American Journal of Respiratory & Critical Care Medicine recommends its use in MDR-TB.