Levofloxacin

Levofloxacin is the L-form of the fluoroquinolone antibacterial agent, ofloxacin. In in vitro studies, levofloxacin demonstrated a broad range of activity against Gram-positive and -negative organisms and anaerobes. The drug is more active against Gram-positive organisms than ciprofloxacin, but less active than newer fluoroquinolones such as gatifloxacin. Its activity against Streptococcus pneumoniae is unaffected by the presence of penicillin resistance.

In several randomised controlled trails, 5 to 14 days’ treatment with intravenous and/or oral levofloxacin proved an effective therapy for upper and lower respiratory tract infections. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once or twice daily was as effective as intravenous and/or oral gatifloxacin, clarithromycin, azithromycin or amoxicillin/clavulanic acid. Overall, clinical response rates with levofloxacin ranged from 86 to 95% versus 88 to 96% with comparator agents; bacteriological response rates were 88 to 95% and 86 to 98%, respectively. Sequential (intravenous ± oral switch) therapy with levofloxacin 750mg once daily was as effective as intravenous imipenem/cilastatin (± oral switch to ciprofloxacin) in patients with severe nosocomial pneumonia. Generally, oral levofloxacin 250 or 500mg once daily was at least as effective as oral cefaclor, cefuroxime axetil, clarithromycin or moxifloxacin in patients with acute exacerbations of chronic bronchitis as assessed by either clinical or bacteriological response rates. This approach also provided similar efficacy to amoxicillin/ clavulanic acid or clarithromycin in patients with acute sinusitis.

Sequential therapy with levofloxacin 500mg twice daily for 7 to 14 days’ was as effective as intravenous imipenem/cilastatin in patients with suspected bacteraemia. Oral levofloxacin 500mg once daily for 7 to 10 days was also an effective treatment in patients with uncomplicated skin and skin structure infections, and in those with complicated urinary tract infections. A higher dosage of sequential levofloxacin 750mg once daily proved as effective as intravenous ticarcillin/clavulanic acid (± oral switch to amoxicillin/clavulanic acid) in the treatment of complicated skin and skin structure infections.

Pharmacoeconomic studies suggest that levofloxacin may be cost-saving in comparison to conventional therapies.

Conclusions: Levofloxacin continues to demonstrate good clinical efficacy in the treatment of a range of infections, including those in which S. pneumoniae is a potential pathogen. Importantly, it has efficacy in CAP similar to that of gatifloxacin and at least as good as that of the third generation cephalosporins. Extensive clinical data confirm the good tolerability profile of this agent without the phototoxicity, hepatic and cardiac events evident with some of the other newer fluoroquinolone agents. Levofloxacin therefore offers a unique combination of documented efficacy and tolerability, and provides an important option for the treatment of bacterial infections.

The minimum concentration of levofloxacin required to inhibit the growth of 90% of strains (MIC90) for methicillin-sensitive Staphylococcus aureus, Streptococcus pyogenes, S. pneumoniae and viridans or β-haemolytic streptococci was ≤2 mg/L (susceptibility breakpoint). The activity of levofloxacin against S. pneumoniae was not affected by the presence of penicillin resistance; 99.4% of 9499 S. pneumoniae isolates were sensitive to levofloxacin in one study. Against other Gram-positive organisms, levofloxacin tended to be more active than ciprofloxacin but 2- to 4-fold less active than other newer fluoroquinolones such as moxifloxacin and gatifloxacin.

Levofloxacin was active against 96.1% of 5034 Enterobacteriaceae isolates in one survey, with MIC90 values of <0.5 to 2 mg/L. Levofloxacin is also highly active against \-lactamase-positive and -negative strains of Haemophilus influenzae (mean MIC₉₀ ≤0.5 mg/L) and Moraxella catarrhalis (mean MIC90 ≤0.5 mg/L), and is at least as active as ciprofloxacin and ofloxacin against anaerobic and intracellular bacteria. Like most other fluoroquinolones, levofloxacin shows limited antibacterial activity against Pseudomonas aeruginosa, Acinetobacter spp. and Stenotrophomonas maltophilia.

Less than 1% of S. pneumoniae (9499 isolates), H. influenzae (1934) and M. catarrhalis (1108) isolates collected in the US between 1999 and 2000 were resistant to levofloxacin. Importantly, levels of S. pneumoniae resistance to levofloxacin were generally low throughout the world in ≈5000 isolates. For example, of 17 943 S. pneumoniae isolates collected from 1997 to 2000 in the US, only 0.7% were resistant to levofloxacin; this level of resistance was 5-fold lower than that to ceftriaxone, more than 20-fold lower than penicillin resistance and 35-fold lower than that for azithromycin or cotrimoxazole.

Levofloxacin 500mg once daily for 7 days significantly reduced numbers of both enterococci and enterobacteria in the intestinal microflora of ten healthy volunteers, with partial suppression of clostridia.

In patients with pulmonary, skin and skin structure, and urinary tract infections receiving clinically relevant dosages of levofloxacin, maximum plasma concentration (C_max):MIC ratios of >12.2 produced rates of clinical and bacteriological cure of ≥99% in a prospective study. Greater than 97, >99 and >99% of S. pneumoniae, H. influenzae and M. catarrhalis isolates, respectively, were susceptible to levofloxacin according to area under the plasma concentration-time curve (AUC):MIC ratios for Gram-positive (ratio ≥30) and -negative (>100) organisms in vitro.

Levofloxacin shows a postantibiotic effect against S. pneumoniae, S. aureus, S. epidermidis, Enterococcus faecalis, Escherichia coli and Legionella pneumoniae. In in vitro studies, levofloxacin is rapidly bactericidal against S. pneumoniae at concentrations of 2 to 8 times the MIC, achieving a 99% killing rate within 0.9 to 6 hours; bactericidal activity was not affected by the presence of penicillin resistance.

The bioavailability of levofloxacin is ≥99% following oral administration. Oral or intravenous levofloxacin has linear pharmacokinetics over the therapeutic dosage range (100 to 1000 mg/day); after single dose levofloxacin 500mg, mean maximum plasma concentration (Cmax) values ranged from 4.5 to 7.6 mg/L in healthy volunteers or patients. In healthy volunteers, steady-state C_max(5.7 mg/L) was attained within 48 hours following multiple doses of oral levofloxacin 500mg once daily. Like other newer fluoroquinolones, C_max and AUC values were significantly (p < 0.01 both comparisons) higher after a single dose of levofloxacin 500mg than after a single dose of ciprofloxacin 250mg.

Levofloxacin distributes rapidly and extensively into tissues throughout the body including lung, skin, maxillary sinus, sputum and alveolar macrophages; a notable exception is its relatively poor penetration of the CSF. Concentrations in tissues are generally markedly higher than those seen in the plasma and are usually many times greater than the MICs of bacterial pathogens commonly found at these sites. After a single oral dose of levofloxacin 500mg, the mean volume of distribution is 88 to 96.7L. Approximately 24 to 38% of levofloxacin is bound to plasma proteins.

The drug undergoes limited metabolism and is primarily excreted renally. The elimination half-life after single or multiple doses of levofloxacin 500mg ranged from 6.4 to 7.4 hours and 6.9 to 7.6 hours, respectively.

The mean total body clearance for levofloxacin 500mg (oral or intravenous administration) ranges from 8.4 to 11.9 L/h in healthy volunteers, with mean renal clearance of 5.7 to 7.5 L/h. The renal clearance of levofloxacin decreases with increasing renal impairment; dosage reductions are necessary in patients with significant renal impairment. The pharmacokinetics of levofloxacin are not affected by age (in those with normal renal function) or gender in healthy adult volunteers.

Fluoroquinolones can chelate alkaline earth and transition metal cations; the absorption of levofloxacin is reduced by coadministration with aluminium hydroxide in healthy volunteers, although to a lesser degree than that observed with ciprofloxacin. No clinically significant interactions between levofloxacin and theophylline, warfarin or digoxin have been reported.

Randomised comparative trials in adult patients confirm the efficacy of intravenous and/or oral levofloxacin in a range of infections including community-acquired pneumonia (CAP), nosocomial pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis (AECB), uncomplicated and complicated skin or skin structure infections, complicated urinary tract infections (UTIs) and sepsis. All data are for evaluable patients unless stated otherwise.

In patients with severe CAP, sequential (intravenous ± oral switch) therapy with levofloxacin 500mg once daily for 7 to 14 days was at least as effective as treatment for the same duration with intravenous or intramuscular ceftriaxone 1000 to 2000 mg/day plus intravenous erythromycin 2000 to 4000 mg/day switched to oral amoxicillin/clavulanic acid 1750 mg/day plus oral clarithromycin 1000 mg/day. Respective clinical response rates were 90 versus 83% in on-treatment groups in this nonblind, multicentre trial.

When analysed by pathogen, oral or intravenous levofloxacin 500mg once daily for 7 to 14 days was effective against CAP caused by Mycoplasma pneumoniae, Legionella spp., Chlamydophila (Chlamydia)pneumoniae or penicillin-or macrolide-resistant strains of S. pneumoniae.

Sequential therapy with levofloxacin 750mg once daily was as effective as imipenem/cilastatin (± switch to oral ciprofloxacin) in 438 patients with severe nosocomial pneumonia. In this randomised, nonblind, multicentre trial, clinical and bacteriological response rates with levofloxacin were 59 and 67% versus 63 and 61% with imipenem/cilastatin in on-treatment groups.

Oral levofloxacin (250 or 500mg once daily) produced a good clinical response rate in patients with AECB in several randomised comparative trials, the majority of which were double-blind. Five to 10 days’ treatment with the drug was as effective as treatment of similar duration with other oral agents including moxifloxacin, cefaclor, cefuroxime axetil and clarithromycin. Clinical response rates with levofloxacin ranged from 70 to 100% versus 61 to 93% with these comparator agents; respective ranges for bacteriological response rates were 63 to 96% and 48 to 96%. Significantly more levofloxacin (500mg once daily) recipients achieved a bacteriological response in one trial [77 vs 60% with cefuroxime axetil 250mg twice daily; 95% confidence interval (CI) 4, 30%]. Notably, clinical (83 vs 85% of patients) and bacteriological (82 vs 83%) response rates were similar after 5 versus 7 days’ treatment with oral levofloxacin 500mg once daily in a randomised, double-blind study in 532 patients with AECB.

In patients with acute sinusitis, 10 to 14 days’ treatment with oral levofloxacin 500mg once daily was as effective as oral amoxicillin/clavulanic acid (500/125mg three times daily) or clarithromycin (500mg twice daily) in three randomised trials; clinical response rates ranged from 88 to 96% with levofloxacin versus 87 to 94% with comparators in on-treatment analyses. Bacteriological efficacy was not assessed in these studies.

Other infections: Treatment with intravenous levofloxacin 500mg twice daily, with or without a subsequent switch to oral administration, was as effective as intravenous imipenem/cilastatin 1g three times daily in a randomised, nonblind trial in patients with suspected bacteraemia; clinical responses were achieved in 77 and 68% of recipients, respectively, and bacteriological responses by 87 and 84%. In addition, the median time from the start of treatment to the time of hospital discharge was significantly shorter with levofloxacin than with imipenem/cilastatin (9 vs 11 days, p = 0.015).

Oral levofloxacin (250 or 300 mg/day) was at least as effective as oral ciprofloxacin (1000 mg/day), gatifloxacin (400 mg/day) or lomefloxacin (400 mg/day) in patients with complicated UTIs in three randomised trials; 87 to 93% of patients had a satisfactory clinical response with levofloxacin compared with 89 to 95% of those receiving a comparator agent. Bacteriological eradication occurred in 94 and 95% of levofloxacin recipients versus 92 to 94% of those receiving ciprofloxacin or lomefloxacin in two trials; the other study found no between-group differences in the per pathogen eradication rate.

Intravenous levofloxacin 500mg once daily was associated with significantly lower mean total costs than intravenous ceftriaxone 1 to 2g once daily ($US6012 vs $US7422, p = 0.048; 1997 values) in a randomised, nonblind, multicentre study in 178 inpatients with CAP. Mean total direct costs per patient also tended to be lower with oral levofloxacin (500mg once daily) than with oral cefuroxime axetil (500mg twice daily) treatment in 210 outpatients with CAP ($US716 vs $US883, p = 0.094; 1997 values).

In patients with CAP, a critical pathway comparing levofloxacin with conventional management resulted in cost savings per patient of $Can457 (hospital perspective) to $Can994 (government perspective) [1998 values], depending on whether a healthcare system, government or societal perspective was taken.

Levofloxacin was generally well tolerated in clinical trials. Most adverse events have typically been transient and mild to moderate in severity. The most common adverse events considered to be drug-related that were reported during phase III clinical trials were nausea (1.3%) diarrhoea (1.1%), vaginitis (0.7%), pruritus (0.5%), abdominal pain (0.4%), dizziness (0.4%), flatulence (0.4%) and rash (0.4%). The overall incidence of levofloxacin-related adverse events was 6.2%, with less than 4% of patients discontinuing treatment because of adverse events attributable to levofloxacin.

The nature, incidence and severity of adverse events was generally similar with once- or twice-daily oral levofloxacin 500mg in patients with CAP. In a retrospective analysis of phase III clinical trials and postmarketing surveillance data, intravenous and/or levofloxacin at a higher dosage (750mg once daily; n = 439) was generally as well tolerated as lower dosages (250 to 500mg once or twice daily; n = 4515).

Levofloxacin appears to have a low potential for phototoxic reactions, and levofloxacin-associated tendinitis and/or tendon rupture is also uncommon. Other rare adverse events documented during levofloxacin therapy include pseudo-membraneous colitis and haemolytic anaemia. Furthermore, abnormal hepatic function associated with levofloxacin-treatment is rare, as confirmed by post-marketing surveillance data.

Cardiac adverse events associated with levofloxacin treatment also appear rare according to postmarketing surveillance studies. One case of levofloxacin-associated QTc interval prolongation has been reported in an 88-year-old woman with atrial fibrillation, bronchitis and mild congestive heart failure; the QTc interval returned to the baseline value after treatment discontinuation. There has also been a case report of levofloxacin-induced intermittent polymorphic ventricular tachycardia with a normal QTc; these symptoms disappeared upon discontinuation of levofloxacin-treatment. Rare episodes of torsades de pointes have been reported during levofloxacin treatment (in patients receiving concomitant treatment), although the relationship to levofloxacin has not been established.

Furthermore, single doses of levofloxacin 500 or 1000mg had no clinically relevant effects on the QTc interval in two randomised, double-blind, crossover studies in healthy adult volunteers. In one study, respective mean changes in QTc interval from baseline after single doses of levofloxacin 500 or 1000mg, or placebo were 1.36, 2.81 and −0.69 msec. The other study showed levofloxacin 1000mg had similar effects on the QTc interval to those seen with ciprofloxacin 1500mg or placebo, whereas moxifloxacin 800mg caused a significant (p < 0.001 for both comparisons) prolongation of the QTc interval versus both fluoroquinolone agents. Mean changes from baseline in the QTc interval with levofloxacin, ciprofloxacin, moxifloxacin and placebo were 3.88,2.27,16.34 and −1.25 msec, respectively.

Levofloxacin is available in both oral and intravenous forms. Guidelines for levofloxacin usage vary according to the country; in the US, oral and/or intravenous levofloxacin 500mg once daily is recommended for the treatment of patients with AECB (administered for 7 days), CAP (7 to 14 days), acute sinusitis (10 to 14 days) and uncomplicated skin or skin structure infections (7 to 10 days). In patients with complicated skin and skin structure infections, 7 to 14 days’ treatment with intravenous or oral levofloxacin 750mg once daily is recommended. Intravenous or oral levofloxacin 250mg once daily is recommended for patients with uncomplicated or complicated UTIs (for 3 and 10 days, respectively).

In Europe, oral levofloxacin 250 to 500mg once daily for 7 to 10 days is recommended for patients with AECB, and 500mg once daily for 10 to 14 days in patients with acute sinusitis. Oral or intravenous levofloxacin is recommended for patients with CAP (500mg once or twice daily for 7 to 14 days), uncomplicated skin and skin structure infections (250 or 500mg once daily, or 500mg twice daily, for 7 to 14 days) or complicated UTIs (250mg once daily for 7 to 10 days). No dosage adjustments are required in elderly patients or in those with hepatic impairment.

Patients with renal impairment (creatinine clearance ≤3 L/h) require modifications of levofloxacin dosage. Levofloxacin is contraindicated in those <18 years of age, patients with epilepsy, those with a history of tendon disorders related to fluoroquinolone administration and women who are pregnant or breastfeeding. Preparations containing di- or trivalent cations should not be taken within 2 hours of levofloxacin administration. Caution is also advised when levofloxacin is being taken concomitantly with theophylline or nonsteroidal anti-inflammatory drugs.