Levofloxacin

Abstract

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. Levofloxacin, the L-isoform of the fluoroquinolone antibacterial agent ofloxacin, inhibits both bacterial DNA gyrase and topoisomerase IV. The primary target of action depends on the type of bacteria. 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 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...