Department of Chest and Infectious Diseases, Chest Hospital Heckeshorn, Central Clinic Emil von Behring, Zum Heckeshorn 33, 14109 Berlin, Germany
The impact of respiratory infections on inviduals in society is important and is growing as the population ages. Lower respiratory tract infections in particular are major causes of morbidity and mortality. These infections include acute exacerbation of chronic bronchitis (AECB) and community-acquired pneumonia. Of the two conditions, AECB is more prevalent, occurring in 46% of the population over 65 years old in Germany, with an average of 2.4 acute exacerb- ations per patient each year. In the UK, chronic bronchitis causes 5% of deaths and is responsible for 28 million lost working days per year.
Community-acquired respiratory tract infections (RTIs) may be caused by Gram-positive organisms (predominantly Streptococcus pneumoniae), Gram-negative organisms (Haemophilus influenzae and Moraxella catarrhalis) and atypical bacteria (e.g. Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae). In community-acquired pneumonia (CAP) pathogens, penicillin resistance has emerged worldwide among pneumococci, while ß-lactamase production among H. influenzae, M. catarrhalis and many Gram-negative bacilli has led to alterations in first-line therapy options.
Although the quinolone class of drugs has been in existence since 1962, only since the fluorination of the molecule in 1983 has the class been considered a major antibacterial group. The classic fluoroquinolones such as ciprofloxacin, norfloxacin, fleroxacin and ofloxacin have had strong activity against Gram-negative bacteria, but the effectiveness of these compounds against Gram-positive bacteria has been debated. The fluoroquinolones developed during the 1990s, notably levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin, have demonstrated enhanced activity against the most common bacteria involved in lower respiratory tract infection (LRTI). The mechanism of newer fluoroquinolone activity is the inhibition of essential bacterial type II topoisomerases (DNA gyrase) and topoisomerase IV. The in vitro antibacterial activity of all new fluoroquinolones against respiratory pathogens is excellent (Table 1). S. pneumoniae MIC90s are reported to be from 0.016 (gemifloxacin) to 0.25 mg/L for moxifloxacin, 0.5 mg/L for gatifloxacin and 12 mg/L for levofloxacin. This activity also includes penicillin- and macrolide-resistant pneumococci. New fluoroquinolones are highly active against H. influenzae and M. catarrhalis, with MIC90s < 0.1 mg/L. In addition, against atypical pathogens the MIC90s are usually <0.125 mg/L for all substances.1
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The clinical efficacy of the newer fluoroquinolones in the treatment of LRTI has been demonstrated in several randomized, double-blind, prospective studies. In comparative CAP studies newer fluoroquinolones almost always outperform the cephalosporins (e.g. ceftriaxone, cefaclor or cefuroxime axetil), other ß-lactam antibiotics (e.g. amoxicillin or co-amoxiclav), the macrolides (e.g. erythromycin or roxithromycin), the older quinolones (ofloxacin) or drug combinations (amoxicillin plus ofloxacin).3 Although differences in efficacy are not always found to be statistically significant, it is clinically of note that every one of the standard comparators required more than once-daily dosing. In a report comparing two fluoroquinolones (one new and one older) in hospitalized and ambulatory patients with CAP, gatifloxacin (400 mg qds, iv/po) and levofloxacin (500 mg qds, iv) achieved statistically equivalent cure rates: 96% for gatifloxcin versus 94% for levofloxacin. Gatifloxacin had a higher cure rate in cases of severe CAP (95% versus 91%), but was slightly less effective in patients >65 years old with significant morbidity.5
Subsequently, Niederman et al.6 compared hospitalization and mortality in patients with CAP being treated with moxifloxacin, amoxicillin or clarithromycin. From pooled data subjected to meta-analysis (from four multinational trials), the mortality rate for moxifloxacin-treated patients was significantly better (P = 0.045) than for comparator-treated patients. Moxifloxacin-treated patients were also less likely to be hospitalized. Gemifloxacin was compared with trovafloxacin for the treatment of CAP.7 At follow up, for clinical and radiological response, gemifloxacin 320 mg once-daily was as effective as trovafloxacin 200 mg once-daily (both for 714 days) in the treatment of patients with CAP. Analysis of the intent-to-treat population indicated that gemifloxacin (87.6%) was statistically significantly superior to trovafloxacin (81.1%) based on clinical and radiological efficacy.
In a recent North American study of gatifloxacin (400 mg qds po for 710 days) versus cefuroxime axetil (250 mg qds po for 710 days) for the treatment of acute exacerbation of chronic bronchitis (AECB), cure rates were substantially higher for gatifloxacin (89% versus 77%). In those with documented S. pneumoniae infection the difference was even more pronounced; cure rates were 100% for the gatifloxacin recipients and only 38% for cefuroxime axetil recipients.8 Wilson et al.9 compared 5 days of moxifloxacin (400 mg od) with 7 days of clarithromycin (500 mg bd) in 750 patients with AECB. Clinical cure was achieved in 89% of the moxifloxacin group compared with 88% of the clarithromycin group. Bacteriological response 7 days post-treatment was 77% in the moxifloxacin group, compared with 62% in the clarithromycin group, thereby indicating the superiority of moxifloxacin. Gemifloxacin was compared with trovafloxacin for the effective short course treatment of AECB.10 In this study gemifloxacin 320 mg once-daily for 5 days was compared with trovafloxacin 200 mg od for 5 days. The clinical success rate in the intent-to-treat group was 89.4% for gemifloxacin versus 83.1% for trovafloxacin, a statistically significant difference. Bacteriological response in the intent-to-treat group was 83.6% for gemifloxacin-treated patients and 74.1% in the trovafloxacin group.
The adverse event profile associated with the fluoroquinolones includes gastrointestinal upset, headache, rash and pruritus. Less frequently seen problems include renal disturbances, tendinitis, hypersensitivity reactions, photosensitivity, convulsions, psychosis and certain drug interactions.11
Nausea and diarrhoea were the most frequent adverse events, ranging from 1.2% for levofloxacin to 8% for gatifloxacin and moxifloxacin, and 1.2% for levofloxacin to 6% for moxifloxacin. The rate of overall adverse events was 29.9% from US and European data, compared with 3.7% from Japanese data. An important observation for gatifloxacin, gemifloxacin and moxifloxacin is the absence of phototoxicity and liver toxicity, and mean QT-prolongation values of not more than 26 ms.
Current treatment guidelines for the management of LRTI in adults recommend fluoroquinolones for empirical therapy in several patient groups. In the guidelines of the European Respiratory Society,12 the newer fluoroquinolones are suggested as alternatives to the use of aminopenicillin in patients with community-acquired LRTI managed at home, whereas the older quinolones are recommended in patients who are managed in the hospital setting. Recent guidelines from the American Thoracic Society on the management of CAP in adults13 state that fluoroquinolones are among the preferred agents for the empirical treatment of such patients who have risk factors for infection by penicillin- and macrolide-resistant pathogens.
The new fluoroquinolones currently available offer major therapeutic advances compared with previous agents, and the incidence of adverse events is clearly outweighed by their clinically utility. As with other antibiotics, the development of resistance is a potential problem associated with their increased use in RTIs. Rational and thoughtful prescribing, and continous control of antibiotic resistance levels are needed to sustain their future antibacterial efficacy.
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Wise, R. & Honeybourne, D. (1999). Pharmacokinetics and pharmacodynamics of fluoroquinolones in the respiratory tract. European Respiratory Journal 14, 2219.
3 . Blondeau, J. M. (2001). Clinical utility of the new fluoroquinolones for treating respiratory and urinary tract infections. Expert Opinion on Investigational Drugs 10, 21336.[ISI][Medline]
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Preston, S. L., Drusano, G. L., Berman, A. L., Fowler, C. L., Chow, A. T., Dornseif, B. et al. (1998). Levofloxacin population pharmacokinetics and creation of a demographic model for prediction of individual drug clearance in patients with serious community-acquired infection. Antimicrobial Agents and Chemotherapy 42, 1098104.
5 . Sullivan, J. G., McElroy, A. D., Honsinger, R. W., McAdoo, M., Harrison, B. J., Plouffe, J. F. et al. (1999). Treating community-acquired pneumonia with once-daily gatifloxacin vs. once-daily levofloxacin. Journal of Respiratory Diseases 20, Suppl. 5, 4959.
6 . Niederman, M., Church, D., Haverstock, M. & Springsklee, M. (2000). Does appropriate antibiotic therapy influence outcome in community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB)? Journal of Respiratory Medicine 94, Suppl. A, E23.
7 . File, T., Schlemmer, B., Garau, J., Siquier, B., Hendrick, K. & Young, C. (2000). Efficacy of once-daily gemifloxacin in the treatment of community-acquired pneumonia. The gemifloxacin 049 study group. In Third European Congress of Chemotherapy, Madrid, Spain, 710 May 2000. Abstract M129.
8 . DeAbate, C. A., McIvor, R., McElvaine, P., Skuba, K. & Pierce, P. (1999). Gatifloxacin vs cefuroxime axetil in patients with acute ex-acerbations of chronic bronchitis. Journal of Respiratory Medicine 94, Suppl. A, E23.
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Wilson, R., Kubin, R., Ballin, I., Deppermann, K. M., Bassaris, H. P., Leophonte, P. et al. (1999). Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute excerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 44, 50113.
10 . Ball, P., Wilson, R., Mandell, L. A. & Tillotson, G. (2000). Effective short-course therapy of acute exacerbation of chronic bronchitis (AECB) with once-daily gemifloxacin. In Third European Congress of Chemotherapy, Madrid, Spain, 710 May 2000. Abstract M125.
11 . Ball, P., Mandell, L., Niki, Y. & Tillotson, G. (1999). Comparative tolerability of the newer fluoroquinolone antibacterials. Drug Safety 21, 40721.[ISI][Medline]
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European Study on Community-Acquired Pneumonia Committee. (1998). Guidelines for management of adult community-acquired lower respiratory tract infections. European Respiratory Journal 11, 98691.
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American Thoracic Society. (2001). Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. This official statement of the American Thoracic Society was approved by the ATS Board of directors. American Journal of Respiratory Critical Care Medicine 163, 173054.
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Wise. R. & Honeybourne, D. (1999). Pharmacokinetics and pharmacodynamics of fluoroquinolones in the respiratory tract. European Respiratory Journal 14, 2219.