Levofloxacin possesses a broad spectrum of activity against many common pathogens and attains exceptionally high intracellular and tissue levels following oral administration. The bactericidal effect of levofloxacin is concentration-dependent. This means that if the dose is increased, it is possible to increase peak concentration, which is associated with even better tissue concentration and a possible reduction in the development of resistance. High-dose levofloxacin provides an effective treatment for severe infections by exploiting these pharmacokinetic features.

CONTENTS

• Pharmacokinetic profile suggests a role for high-dose levofloxacin
• When does the physician need high dose levofloxacin?

Pharmacokinetic profile suggests a role for high-dose levofloxacin

Levofloxacin has proven to be an extremely useful antimicrobial. It is effective and safe in the treatment of a wide variety of infections. This is not true for all fluoroquinolones, many of which have been removed from the market due to unacceptable side effects. Concerns about side effects have resulted in the use of moderate doses. However, levofloxacin has been shown to be safe when prescribed in higher doses of 750 mg and 1,000 mg/day, making it advantageous. Research and clinical experience has shown that high-dose fluoroquinolone therapy may be indicated in certain situations. These include very large patients, who due to their large physical size require higher doses to provide effective therapy. Patients with serious infections requiring admission to ICU may also require high-dose therapy because of altered pharmacokinetic profiles or difficult to treat causative pathogens (6). This is supported by data from a recent study that analyzed eight patients with sepsis. The study revealed that individual values of tissue penetration were highly variable and, while the usual dose may be sufficient for Staphylococcus aureus, higher doses may be required for infections due to Pseudomonas aeruginosaor Enterobacter spp. (7). The pharmacokinetic characteristics of parenteral levofloxacin were analyzed in another important study that compared data from ICU patients, healthy volunteers and those with lower respiratory tract infections (LRTIs). Results confirmed that levofloxacin 500 mg b.i.d. achieved an area under the curve (AUC) of 67.80 mg•h/l in ICU patients and AUC of 49.60 mg•h/l in healthy volunteers. In those with an LRTI the AUC was 74.97 mg•h/l, which supports administration of higher doses to ICU patients. Further pharmacokinetic data has been reported comparing 500 mg levofloxacin o.d. with 750 mg and 1,000 mg levofloxacin o.d., all given for 10 days of therapy (8). Results demonstrated marked differences in pharmacokinetic features; a linear relationship was noted. The maximum concentration (Cmax) values for the 500 mg, 750 mg and 1,000 mg doses were 5.7 mg/l, 8.6 mg/l and 11.8 mg/l respectively, and the AUC values were 48 mg•h/l, 91 mg•h/l and 118 mg•h/l respectively. Therefore as the dose increases, the plasma and tissue levels rise correspondingly. An important study of steady-state plasma and lung concentrations of fluoroquinolones in 36 volunteers investigated 500 mg and 750 mg levofloxacin, and 500 mg ciprofloxacin b.i.d. Concentrations in epithelial lining fluid at 12 hours were 6.5 mg/l for 500 mg levofloxacin, rising to 9.2 mg/l for 750 mg levofloxacin, but a staggeringly low 0.4 mg/l for the 500 mg ciprofloxacin b.i.d. schedule (9). Therefore the drug distribution in the lung is much better for levofloxacin. This pharmacokinetic data supports the rationale for using higher dose levofloxacin therapy, particularly in severe infections (such as nosocomial pneumonia) or those with difficult to treat pathogens such as Klebsiella pneumoniae.

When does the physician need high dose levofloxacin?

A large US study comparing levofloxacin 750 mg with imipenem/cilastatin 500-1,000 mg assessed 438 patients. There was a 58% bacteriological eradication rate in the levofloxacin group and a 61% eradication rate in the imipenem/cilastatin arm (Table 2) (10). Among those clinically evaluable, 60% of the levofloxacin patients were successfully treated compared to 63% in the imipenem/cilastatin arm. Therefore in these very difficult to treat patients with other co-morbidities, levofloxacin 750 mg o.d. was equivalent to imipenem/cilastatin 500-1,000 mg t.i.d., switching to oral ciprofloxacin 750 mg b.i.d. The 750 mg levofloxacin regimen was also well tolerated with the incidence of reported adverse drug reactions (ADRs) less than 5%.

Table 2. Post-therapy clinical response rates (3-15 days after last dose)

Levofloxacin 750 mg o.d. may be useful in other infections, including complicated skin and skin structure infections (CSSSIs), as it is able to achieve higher concentrations in wound tissue than in blood (11). A study comparing levofloxacin 750 mg versus ticarcillin/clavulanic acid 3.1 g q.i.d. reported clinical success rates of 84% for levofloxacin and 80% for the comparator (12). Microbiological success with levofloxacin was also higher at 84% compared to 71% for the ticarcillin arm. Meningitis is another infection that may warrant the use of high dose levofloxacin. A study assessing levofloxacin 500 mg b.i.d. measured the steady-state concentrations of levofloxacin in plasma and cerebrospinal fluid (CSF) of five patients with acute bacterial meningitis. It found that by using this higher dose, levofloxacin reached levels between 1-2.5 mg/l in CSF and 4-7 mg/l in plasma (13). Although only a small pilot study, these results indicate levofloxacin’s potential use in treating such infections. High-dose levofloxacin therapy may also play a role in managing nosocomial pneumonia; some cases of community-acquired pneumonia (CAP), especially with the aim of shortening the duration of therapy; Legionellosis; endocarditis due to viridans group streptococci; and Pseudomonas aeruginosa infection. Therefore, while the normal dosage of levofloxacin is 500 mg o.d., in certain clinical situations it may be preferable to use a higher dose of 750 mg. This dose has been used quite safely in a number of patients and data supporting its efficacy and safety is growing. The tolerability of levofloxacin appears to be very good with an overall low incidence of side effects with the 750 mg dose and even at higher doses of 1,000 mg/day.

References
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