The role of antibiotics in COPD exacerbations

teaser

Mario Cazzola
MD
Consultant in Respiratory
Medicine and Chief of Respiratory
Clinical Pharmacology
Department of Respiratory Medicine
A Cardarelli Hospital
Naples, Italy
Visiting Senior Research Fellow
Sackler Institute of Pulmonary
Pharmacology
GKT School of Biomedical Sciences
London, UK
Chairman
Airway Pharmacology and Treatment Group
European Respiratory Society
E: [email protected]

The specific role that bacterial infections play in acute exacerbations of COPD (AECOPD) is controversial.(1) Consequently, the efficacy of antibiotic therapy in AECOPD is also questionable.(2) Nevertheless, antibiotics are usually prescribed because of the lack of clinical features that can be used to discriminate between those patients who are infected and those who are not. There is a subgroup of patients who are less likely to spontaneously recover from an exacerbation, but it cannot be characterised.(3) For these reasons, between 80% and 100% of outpatients with AECOPD receive an antibiotic, usually a β-lactam, although between 13% and 25% return promptly complaining of continuing symptoms.(4,5) Bacterial resistance to the prescribed antibiotic might explain this.(6) Another explanation may be that airway inflammation is poorly controlled, despite successful eradication of any bacterial infection that is present.

A body of evidence supports the use of antibiotics in AECOPD for any patient with at least two of the three cardinal symptoms of exacerbation,(7) which are:

• Increased dyspnoea.
• Increased sputum volume.
• Increased sputum purulence.(8)

Patients with more severe exacerbations are those who more likely to experience benefit.(9)

Choosing an antibiotic
The aim of antimicrobial therapy is to reduce the duration of symptoms and induce a fast microbiological recovery. Since it is often difficult to obtain sputum samples with which to identify pathogens causing AECOPD, initial antimicrobial therapy is usually empirical.(10) The choice of an antibiotic must consider many factors, such as the likely bacterial aetiology, the possibility of resistant microorganisms, the severity of the infection, the underlying comorbidity and the need of hospitalisation.(11) Moreover, tolerance of the compound, its pharmacokinetics and cost also influence this choice.

While the choice of an antimicrobial is empirical, it must also be rational. Antibiotic therapy should be  initiated based on patient history, the severity of the exacerbation and trends of bacterial resistance in the community where the patient lives. The degree of functional respiratory impairment may also be used in the selection of empirical antibacterial treatment for AECOPD.(12–14) Whereas a higher rate of Enterobacteriaceae and Pseudomonas species parallels worse lung function in patients with COPD, patients with
better lung function have significantly more Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis strains in sputum cultures during acute infective exacerbations.(13) Many pneumococci are resistant to penicillins and other agents, while both H influenzae and M catarrhalis are commonly associated with β-lactamase production.(15) Therefore antibiotics covering the whole spectrum of COPD pathogens and capable of overcoming resistance must be chosen for empirical use, particularly in patients with exacerbation accompanied by comorbidity and with more than three or four episodes of AECOPD in the last year. In fact, in this type of patient, resistant organisms can coexist with factors that inactivate antibiotics or reduce their capacity to penetrate into the lung.(16)

The choice of an antibiotic in the treatment of AECOPD can affect the treatment outcome. In the early 1980s, no differences in outcome among the usual firstline antibiotics, which included amoxicillin/ampicillin, co-trimoxazole and erythromycin, and secondline agents, such as early-generation oral cephalosporins, were observed. With the development of resistance, it might be expected that newer antibiotics would do better than older drugs. Although the traditional firstline agents may still prove to be the most cost-effective option in younger immunocompetent subjects, in patients with comorbidities or more severe disease, they may often be inappropriate due to limited spectrum in vitro, a need for frequent dosing, poor tolerance and compliance, and the development of bacterial resistance.(11)

Several stratification schemes identify a patient’s age, the severity of underlying pulmonary dysfunction,frequency of exacerbations and the presence of comorbid illnesses as predictors for likely pathogens and to guide antimicrobial selection.(17) This approach, together with the use of new antibiotic alternatives, such as co-amoxiclav, the newer macrolides and the newer fluoroquinolones, in patients with cardiopulmonary comorbidity and/or moderate to severe alterations of lung function (FEV(1) < 50%), may reduce the likelihood of treatment failure, with significant medical and economic implications (see Figure 1). Conversely, outpatients without any comorbidity but with at least two cardinal symptoms are likely to be cured with an oral β-lactam. These antibiotics are cheap and effective, although their use is problematic because of the increasing incidence of multiresistant S pneumoniae and β-lactamase-producing H influenzae.(17) The marginal pharmacokinetics of oral β- lactams in the respiratory tract equally limits their use, particularly in the compromised patient.(18)

[[HPE08_fig1_36]]

Conclusion
Exacerbations of COPD are costly, but the greatest part of costs derives from therapeutic failures, particularly those that end in hospitalisation.(19,20) A report by Destache et al demonstrated that outpatients with AECOPD treated with firstline therapy (including amoxicillin, co-trimoxazole, tetracycline and erythromycin) had significantly higher failure rates than those treated with thirdline agents (co-amoxiclav, azithromycin and ciprofloxacin).(21) Although pharmacy costs were lowest with firstline agents, thirdline agents showed a trend towards lower mean total cost of AECOPD because they significantly reduced the need for hospitalisation. Moreover, thirdline agents significantly prolonged the time between exacerbations when compared with firstline antimicrobials. Grossman et al found that the use of more expensive antibiotics was a cost-effective strategy in patients with more severe COPD.(22) These agents are also active against Gramnegative bacteria, which are responsible for a significant number of exacerbations in severe patients.

These data indicate that an apparently higher initial cost for the acquisition of more recent drugs reduces the economic burden for the management of COPD because it diminishes the number of exacerbations and, more importantly, the risk of hospitalisation.

References

1. Hirschmann JV. Chest 2000;118:193-203.
2. Schentag JJ, Tillotson GS. Chest 1997;112:314S-19S.
3. Fagon JY, Chastre J, Trouillet JL, Domart Y, et al. Am Rev Respir Dis 1990;142:1004-8.
4. Davey P, Rutherford D, Graham B, et al. Br J Gen Pract 1994;44:509-13.
5. Huchon GJ, Gialdroni-Grassi G, Léophonte P, et al. Eur Respir J 1996;9:1590-5.
6. Ball P, Tillotson G, Wilson R. Presse Med 1995;24:189-94.
7. Murphy TF, Sethi S, Niederman MS. Chest 2000;118:204-9.
8. Anthonisen NR, Manfreda J, Warren CP, et al. Ann Intern Med 1987;106:196-204.
9. McCrory DC, Brown C, Gelfand SE, Bach PB. Chest 2001;119:1190-209.
10. Cazzola M. Infection 1987;15:S113-19.
11. Cazzola M. Pulm Pharmacol 1994;7:139-52.
12. Cazzola M, Ariano R, Gioia V, et al. Clin Ther 1990;12:105-17.
13. Eller J, Ede A, Schaberg T, et al. Chest 1998;113:1542-8.
14. Miravitlles M, Espinosa C, Fernandez- Laso E, et al. Chest 1999;116:40-6.
15. Felmingham D, Gruneberg RN. J Antimicrob Chemother 2000;45:191-203.
16. Ball P. Curr Opin Pulm Med 1996;2:181-5.
17. Niroumand M, Grossman RF. Infect Dis Clin North Am 1998;12:671-88.
18. Miravitlles M, Murio C, Guerrero T, Gisbert R. Chest 2002;121:1449-55.
19. Dewan NA, Rafique S, Kanwar B, et al. Chest 2000;117:662-71.
20. Cazzola M, Blasi F, Allegra L. Respir Med 2001;95:95-108.
21. Destache CJ, Dewan N, O’Donohue WJ, et al. J Antimicrob Chemother 1999;43 Suppl:107-13.
22. Grossman R, Mukherjee J, Vaughan D,et al. Chest 1998;113:131-41.
23. European Respiratory Society W:www.ersnet.org European Society of Clinical Microbiology and Infectious Diseases W:www.escmid.org
24. COPD-Support, Inc W:http://copdsupport.com

Events
13th European
Congress of Clinical
Microbiology and Infectious Diseases
10–13 May 2003
Glasgow, UK
E:[email protected]
13th European Respiratory Society
(ERS) Annual Congress
27 Sept – 1 Oct 2003
Vienna, Austria
E:[email protected]
5th European Congress of Chemotherapy and Infection
17–21 October 2003
Rhodes, Greece
E:[email protected]