Background Information of the Condition
Chronic bronchitis is a subset of chronic obstructive pulmonary disease defined by a productive cough for at least 3 months in duration in each of 2 consecutive years, which may include an acute exacerbation of increased sputum production and purulence, and increased dyspnea. An increased respiratory rate and wheezing, lethargy and elevated temperature are usually indicative of an acute exacerbation of chronic bronchitis, which is usually caused by a virus. Measurement of expiratory flow volume is recommended along with oxygen saturation in moderate to severe cases, whereas sputum cultures are not routinely recommended.1
Category: Levofloxacin, the L-isomer of the racemate ofloxacin, is a member of the fluoroquinolone class of antibiotics.
Mechanism of Action: Levofloxacin exerts its action by inhibiting the bacterial topoisomerases II (DNA gyrase) and topoisomerases IV, which interferes with bacterial DNA replication, transcription, repair, and recombination.
Indications: Levofloxacin is indicated for the treatment of adults with upper and lower respiratory tract, skin/skin structure, and urinary tract infections.
Dose & Duration: The recommended dose is 500mg i.v./oral once daily for 7 days (normal course of therapy) or 750mg i.v./oral once daily for 5 days (short-course therapy).
Methodology of Systematic Review
In double blind randomized controlled trials (DB RCTs), does levofloxacin (normal and short-course therapy) provide a significant therapeutic advantage in terms of mortality or morbidity when compared to other fluoroquinolones or other classes of antibacterial agents in the treatment of adult patients with acute exacerbations of chronic bronchitis?
Assessment principles: Double blind randomized controlled trials comparing levofloxacin to other fluoroquinolones or other classes of antibacterial agents in adult patients with acute exacerbations of chronic bronchitis were critically appraised. Therapeutic impact was assessed according to the following hierarchy of health outcomes – mortality, non-fatal serious adverse events, quality of life, withdrawals due to adverse events, clinical response rates (clinical resolution of signs and symptoms of infection), microbiological response rates (bacteriological eradication of causative pathogen), and other adverse events (e.g. allergic reactions).
Search strategy: Databases searched: Medline, EMBASE and Cochrane Library (from 1966 to February 2008); the manufacturer’s submission, and references of review articles. Key search words included: “levofloxacin” or “Levaquin,” “randomized controlled trial,” and “acute exacerbations of chronic bronchitis.”
Seven DB RCTs met the inclusion criteria, comparing levofloxacin to moxifloxacin, gemifloxacin, azithromycin, or cefuroxime-axetil (Urueta-Robledo et al 2006, Hautamaki et al 2001, Sethi et al 2004, Zervos et al 2005, Amsden et al 2003, Davies et al 1999, and Shah et al 1999).4-10
Levofloxacin versus other fluoroquinolones
Based on three double blind RCTs in 1522 adult patients with acute exacerbations of chronic bronchitis, oral levofloxacin 500mg for 7 days was not significantly different from oral moxifloxacin 400mg daily for 5 days (Urueta-Robledo et al 2006, Hautamaki et al 2001)4, 5 or oral gemifloxacin 320mg daily for 5 days (Sethi et al 2004)6 in terms of mortality, total withdrawals, or withdrawals due to adverse events. Hautamaki et al and Sethi et al showed no significant differences between treatment groups in terms of non-fatal serious adverse events; Hautamaki et al and Urueta-Robledo et al showed no significant differences in clinical or bacteriological response, and Sethi et al showed no significant differences in total adverse events. The clinical success rate in the Sethi et al trial (defined by resolution of signs and symptoms of acute exacerbations of chronic bronchitis not requiring additional antibacterial therapy) was significantly better 28-35 days post therapy (but not at 9-11 or 14-21 days post therapy) with gemifloxacin as compared with levofloxacin (gemifloxacin group, an ARR = 10%, NNT = 10).6
Urueta-Robledo et al did not report non-fatal serious adverse events or total adverse events. Hautamaki et al did not report total adverse events.
Levofloxacin versus other classes of antibacterial agents
Based on four DBRCTs in 1431 randomized adult patients with acute exacerbations of chronic bronchitis, oral levofloxacin 500mg daily for 7-10 days was compared to a single 2000mg dose of oral azithromycin (Zervos et al 2005)7, oral azithromycin 500mg for 1 day then 250mg daily for 4 days (Amsden et al 2003)8, or 500mg of cefuroxime-axetil for 7 days (Davies et al 1999)9 or 7-10 days (Shah et al 1999)10. Zervos et al, Davies et al, and Shah et al showed no significant differences between treatment groups in terms of total mortality. In addition, the Davies et al trial showed no significant differences between treatment groups in terms of non-fatal serious adverse events, clinical or bacteriological response, total withdrawals, withdrawals due to adverse events, or total adverse events. Shah et al did show a statistically significant improvement in the clinical cure rate in patients receiving levofloxacin at the clinical endpoint of 5-14 days post therapy compared with cefuroxime-axetil (levofloxacin group, an ARR = 8%, NNT = 12). The rate of a satisfactory bacteriological response defined as eradication or presumed eradication at 5-14 days and at 21-28 days post therapy was also significantly greater with levofloxacin (levofloxacin group, ARR = 17%, NNT=6 and an ARR=24%, NNT=4, respectively).10
The Zervos et al and Amsden et al trials did not report non-fatal serious adverse events, clinical or bacteriological response, total withdrawals, withdrawals due to adverse events, and total adverse events. Shah et al did not report non-fatal serious adverse events, total withdrawals, and total adverse events. Amsden et al was the only trial to not report on mortality.
In double blind randomized controlled trials, levofloxacin does not differ significantly compared to other fluoroquinolones or other classes of antibiotics in clinically relevant outcomes for the treatment of adult patients with acute exacerbations of chronic bronchitis.
- Guideline for the Diagnosis and Management of: Acute Exacerbation of Chronic Bronchitis (2001). Alberta Clinical Practice Guidelines.
- Product Monograph: Levofloxacin (Levaquin™). Antibacterial Agent. Janssen-Ortho Inc., July 16, 2007.
- eCPS (electronic Compendium of Pharmaceuticals and Specialties), Mar. 2008
- Urueta-Robledo, J., Ariza, H., Jardim, J.R., Caballero, A. et al. Moxifloxacin versus levofloxacin against acute exacerbations of chronic bronchitis: the latin American cohort. Respiratory Medicine, 100: 1504-1511, 2006.
- Hautamaki, D., Bruya, T., Kureishi, A., Warner, J. et al. Short-course (5-day) moxifloxacin versus 7-day levofloxacin therapy for treatment of acute exacerbations of chronic bronchitis. Today’s Therapeutic Trends, 19(2): 117-136, 2001.
- Sethi, S., Fogarty, C. and Fulambarker, A. A randomized, double-blind study comparing 5 days oral gemifloxacin with 7 days oral levofloxacin in patients with acute exacerbation of chronic bronchitis. Respiratory Medicine, 98: 697-707, 2004.
- Zervos, M., Breen, J.D., Jorgensen, D.M. and Goodrich, J.M. Novel, single-dose microsphere formulation of azithromycin versus levofloxacin for the treatment of acute exacerbation of chronic bronchitis. Infectious Diseases in Clinical Practice, 13(3): 115-121, 2005.
- Amsden, G.W., Baird, I.M., Simon, S. and Treadway, G. Efficacy and safety of azithromycin vs levofloxacin in the outpatient treatment of acute bacterial exacerbations of chronic bronchitis. Chest, 123: 772-777, 2003.
- Davies, B.I. and Maesen, F.P.V. Clinical effectiveness of levofloxacin in patients with acute purulent exacerbations of chronic bronchitis: the relationship with in-vitro activity. Journal of Antimicrobial Chemotherapy, 43 (Suppl. C): 83-90, 1999 (dose ranging study).
- Shah, P.M., Maesen, FPV, Dolmann, A., Vetter, N. et al. Levofloxacin versus cefuroxime axetil in the treatment of acute exacerbation of chronic bronchitis: results of a randomized, double-blind study. Journal of Antimicrobial Chemotherapy, 43: 529-539, 1999.