Telithromycin in Acute Exacerbations of Asthma
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《新英格兰医药杂志》
To the Editor: Johnston et al. (April 13 issue)1 report that the treatment of exacerbations of asthma with the ketolide telithromycin (a semisynthetic derivative of erythromycin) is associated with a clinical benefit; the underlying mechanism of effect remains unclear. In the absence of microbiologic explanations, the accompanying editorial by Little2 suggests a role for the immunomodulatory effects of macrolides. We would like to suggest another potential contributory mechanism — variations in drug metabolism. Telithromycin is a strong inhibitor of cytochrome P-450 isoenzyme 3A4 (CYP3A4).3 Two inhaled corticosteroids that are commonly used in clinical practice (budesonide and fluticasone) are metabolized to inactive catabolites, predominantly by CYP3A enzymes in the liver.4 CYP3A4 is also responsible for aliphatic oxidation of the long-acting, inhaled 2-agonist bronchodilator salmeterol, which is extensively metabolized by hydroxylation.5 Drug interactions may reduce CYP3A activity through inhibition or may increase metabolic activity through induction.6 It would be interesting to determine whether inhibition of the metabolism of the above-mentioned drugs by telithromycin could have contributed to the observed clinical benefit.
Gaetano Caramori, M.D., Ph.D.
Alberto Papi, M.D.
Università di Ferrara
44100 Ferrara, Italy
crm@unife.it
References
Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006;354:1589-1600.
Little FF. Treating acute asthma with antibiotics -- not quite yet. N Engl J Med 2006;354:1632-1634.
Kasbekar N, Acharya PS. Telithromycin: the first ketolide for the treatment of respiratory infections. Am J Health Syst Pharm 2005;62:905-916.
Jonsson G, Astrom A, Andersson P. Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver. Drug Metab Dispos 1995;23:137-142.
Manchee GR, Eddershaw PJ, Ranshaw LE, et al. The aliphatic oxidation of salmeterol to alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A. Drug Metab Dispos 1996;24:555-559.
Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-2221.
To the Editor: Although Johnston et al. show a significant reduction in the symptoms of acute exacerbations of asthma with telithromycin, as compared with placebo, they do not explain the beneficial effects of macrolides. An alternative explanation is that asthma is often worsened by chronic gastroesophageal reflux disease (GERD). Telithromycin may reduce GERD through a prokinetic effect. This reduced reflux may result in the improvement of asthma symptoms; similar beneficial effects of macrolides have been noted in patients with chronic asthma.1 We suggest that the best method for isolating the degree of GERD-related benefit would be to conduct a prospective, randomized study comparing macrolide treatment, standard antireflux measures, and placebo during usual asthma therapy. Antireflux measures should consist of the elevation of the head of the patient's bed, acid blockade, and the use of antacids and prokinetic drugs.
Anand Mutgi, M.D.
Jeffrey Hammersley, M.D.
Medical University of Ohio
Toledo, OH 43614
References
Richeldi L, Ferrara R, Fabbri LM, Lasserson TJ, Gibson PG. Macrolides for chronic asthma. Cochrane Database Syst Rev 2005;4:CD002997-CD002997.
To the Editor: We have seen the effectiveness of macrolides in many clinical situations. Although the beneficial effect of macrolides on asthma has been documented for decades, it is known that the effect cannot be explained solely by the antimicrobial effect of the drugs.1,2 The nonantimicrobial effect is not limited to telithromycin but is a property of all macrolides.2 Why did the authors study telithromycin? Furthermore, the decrease in the clearance of theophylline by telithromycin3 should have been mentioned, since such a difference and changes in the concentration of theophylline may have influenced the data analysis and interpretation.
Yukio Kuramochi, M.D.
Toshisada Morita, M.D.
Shizuoka Medical Center
Shizuoka 411-8611, Japan
References
Ferrara G, Losi M, Franco F, Corbetta L, Fabbri LM, Richeldi L. Macrolides in the treatment of asthma and cystic fibrosis. Respir Med 2005;99:1-10.
Blasi F, Cosentini R, Tarsia P, Allegra L. Potential role of antibiotics in the treatment of asthma. Curr Drug Targets Inflamm Allergy 2004;3:237-242.
Nosaka H, Nadai M, Kato M, et al. Effect of a newly developed ketolide antibiotic, telithromycin, on metabolism of theophylline and expression of cytochrome P450 in rats. Life Sci 2006;79:50-56.
To the Editor: Johnston et al. report that telithromycin for the treatment of acute exacerbations of asthma improves symptoms and the forced expiratory volume in one second (FEV1) in the short term. However, we believe that the use of telithromycin for this indication should be strongly discouraged for several reasons. First, although there was a significant improvement in the primary end point (i.e., asthma-symptom scores), the clinical significance was minimal. Second, current recommendations for the treatment of exacerbations of asthma emphasize the early administration of corticosteroids. Yet only 85 of 255 patients (33 percent) received oral corticosteroids, and post hoc analysis revealed no significant benefit in this cohort. Telithromycin might not have been as beneficial in the overall analysis if more patients had received corticosteroids. Moreover, the transient improvement in the FEV1 might have been less impressive with more use of corticosteroids. Finally, overuse may become problematic if physicians initiate antibiotic therapy for exacerbations of asthma. Such therapy could lead to the emergence of resistant pathogens.
Ryosuke Osawa, M.D.
Richard Andraws, M.D.
Beth Israel Medical Center
New York, NY 10003
rosawa-tky@umin.ac.jp
The authors reply: Caramori and Papi are correct in stating that telithromycin is an inhibitor of CYP3A4 and that budesonide, fluticasone, and salmeterol are metabolized by this enzyme. However, we believe that such inhibition is probably not an important contributor to the mechanism of clinical benefit of telithromycin, since studies have shown that a doubling of the dose of inhaled corticosteroids at the onset of an asthma exacerbation has no clinically detectable benefit.1 Therefore, it is unlikely that the partial inhibition of metabolism would achieve a greater exposure to inhaled corticosteroids than would a doubling of the dose. The inhibition of the metabolism of salmeterol is unlikely to be an important mechanism, since only 54 percent of patients who were treated with telithromycin received long-acting -agonists, bronchodilator activity is unlikely to explain the benefit 10 days after the exacerbation, and virus-induced inflammation has a poor response to salmeterol at high doses.2
Mutgi and Hammersley suggest that the effect of prokinetic drugs may have improved exacerbations of asthma, possibly in relation to GERD. Although GERD is associated with frequent exacerbations of severe asthma,3 there is no clear evidence of benefit in the treatment of GERD in patients with stable asthma or exacerbations of asthma. The study they suggest conducting would be interesting in order to determine whether a causal relationship between GERD and exacerbations of asthma exists, since at present such evidence is lacking.
In answer to Kuramochi and Morita, we chose telithromycin because Sanofi-Aventis was willing to sponsor the study; respiratory pathogens are susceptible to telithromycin, whereas macrolide resistance is widespread; and telithromycin may have less potential to select for resistance than do other antibiotics. We doubt whether the inhibition of theophylline metabolism could explain the mechanism of action, since only seven patients who were treated with telithromycin received this drug, which is largely ineffective in exacerbations of asthma.4
In response to the warning by Osawa and Andraws that the use of telithromycin for exacerbations of asthma should be strongly discouraged, we agree that before any clinical recommendation can be made, further studies are needed to confirm our results and to identify patient populations that may benefit. We also agree that a study in which all patients receive oral corticosteroids would be informative. However, we disagree that the clinical benefit was minimal, since the FEV1 improved twice as much in treated patients as in those receiving placebo, and patients receiving telithromycin had a 50 percent improvement in symptoms three days sooner than did those receiving placebo. We hope our findings will stimulate further study so that clearer clinical guidance regarding the role of ketolides and related antibiotics in the treatment of exacerbations of asthma will become available.
Sebastian L. Johnston, M.D., Ph.D.
National Heart and Lung Institute
London W2 1PG, United Kingdom
Richard B. Nieman, M.D.
Berlex
Wayne, NJ 07470
for the Telithromycin, Chlamydophila, and Asthma Trial Investigators
Since publication of the article, Dr. Johnston reports having received grant support from GlaxoSmithKline and AstraZeneca.
References
FitzGerald JM, Becker A, Sears MR, Mink S, Chung K, Lee J. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-556.
Edwards MR, Johnson MW, Johnston SL. Combination therapy: synergistic suppression of virus-induced chemokines in airway epithelial cells. Am J Respir Cell Mol Biol 2006;34:616-624.
ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2005;26:812-818.
Rodrigo C, Rodrigo G. Treatment of acute asthma: lack of therapeutic benefit and increase of the toxicity from aminophylline given in addition to high doses of salbutamol delivered by metered-dose inhaler with a spacer. Chest 1994;106:1071-1076.
Gaetano Caramori, M.D., Ph.D.
Alberto Papi, M.D.
Università di Ferrara
44100 Ferrara, Italy
crm@unife.it
References
Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006;354:1589-1600.
Little FF. Treating acute asthma with antibiotics -- not quite yet. N Engl J Med 2006;354:1632-1634.
Kasbekar N, Acharya PS. Telithromycin: the first ketolide for the treatment of respiratory infections. Am J Health Syst Pharm 2005;62:905-916.
Jonsson G, Astrom A, Andersson P. Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver. Drug Metab Dispos 1995;23:137-142.
Manchee GR, Eddershaw PJ, Ranshaw LE, et al. The aliphatic oxidation of salmeterol to alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A. Drug Metab Dispos 1996;24:555-559.
Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-2221.
To the Editor: Although Johnston et al. show a significant reduction in the symptoms of acute exacerbations of asthma with telithromycin, as compared with placebo, they do not explain the beneficial effects of macrolides. An alternative explanation is that asthma is often worsened by chronic gastroesophageal reflux disease (GERD). Telithromycin may reduce GERD through a prokinetic effect. This reduced reflux may result in the improvement of asthma symptoms; similar beneficial effects of macrolides have been noted in patients with chronic asthma.1 We suggest that the best method for isolating the degree of GERD-related benefit would be to conduct a prospective, randomized study comparing macrolide treatment, standard antireflux measures, and placebo during usual asthma therapy. Antireflux measures should consist of the elevation of the head of the patient's bed, acid blockade, and the use of antacids and prokinetic drugs.
Anand Mutgi, M.D.
Jeffrey Hammersley, M.D.
Medical University of Ohio
Toledo, OH 43614
References
Richeldi L, Ferrara R, Fabbri LM, Lasserson TJ, Gibson PG. Macrolides for chronic asthma. Cochrane Database Syst Rev 2005;4:CD002997-CD002997.
To the Editor: We have seen the effectiveness of macrolides in many clinical situations. Although the beneficial effect of macrolides on asthma has been documented for decades, it is known that the effect cannot be explained solely by the antimicrobial effect of the drugs.1,2 The nonantimicrobial effect is not limited to telithromycin but is a property of all macrolides.2 Why did the authors study telithromycin? Furthermore, the decrease in the clearance of theophylline by telithromycin3 should have been mentioned, since such a difference and changes in the concentration of theophylline may have influenced the data analysis and interpretation.
Yukio Kuramochi, M.D.
Toshisada Morita, M.D.
Shizuoka Medical Center
Shizuoka 411-8611, Japan
References
Ferrara G, Losi M, Franco F, Corbetta L, Fabbri LM, Richeldi L. Macrolides in the treatment of asthma and cystic fibrosis. Respir Med 2005;99:1-10.
Blasi F, Cosentini R, Tarsia P, Allegra L. Potential role of antibiotics in the treatment of asthma. Curr Drug Targets Inflamm Allergy 2004;3:237-242.
Nosaka H, Nadai M, Kato M, et al. Effect of a newly developed ketolide antibiotic, telithromycin, on metabolism of theophylline and expression of cytochrome P450 in rats. Life Sci 2006;79:50-56.
To the Editor: Johnston et al. report that telithromycin for the treatment of acute exacerbations of asthma improves symptoms and the forced expiratory volume in one second (FEV1) in the short term. However, we believe that the use of telithromycin for this indication should be strongly discouraged for several reasons. First, although there was a significant improvement in the primary end point (i.e., asthma-symptom scores), the clinical significance was minimal. Second, current recommendations for the treatment of exacerbations of asthma emphasize the early administration of corticosteroids. Yet only 85 of 255 patients (33 percent) received oral corticosteroids, and post hoc analysis revealed no significant benefit in this cohort. Telithromycin might not have been as beneficial in the overall analysis if more patients had received corticosteroids. Moreover, the transient improvement in the FEV1 might have been less impressive with more use of corticosteroids. Finally, overuse may become problematic if physicians initiate antibiotic therapy for exacerbations of asthma. Such therapy could lead to the emergence of resistant pathogens.
Ryosuke Osawa, M.D.
Richard Andraws, M.D.
Beth Israel Medical Center
New York, NY 10003
rosawa-tky@umin.ac.jp
The authors reply: Caramori and Papi are correct in stating that telithromycin is an inhibitor of CYP3A4 and that budesonide, fluticasone, and salmeterol are metabolized by this enzyme. However, we believe that such inhibition is probably not an important contributor to the mechanism of clinical benefit of telithromycin, since studies have shown that a doubling of the dose of inhaled corticosteroids at the onset of an asthma exacerbation has no clinically detectable benefit.1 Therefore, it is unlikely that the partial inhibition of metabolism would achieve a greater exposure to inhaled corticosteroids than would a doubling of the dose. The inhibition of the metabolism of salmeterol is unlikely to be an important mechanism, since only 54 percent of patients who were treated with telithromycin received long-acting -agonists, bronchodilator activity is unlikely to explain the benefit 10 days after the exacerbation, and virus-induced inflammation has a poor response to salmeterol at high doses.2
Mutgi and Hammersley suggest that the effect of prokinetic drugs may have improved exacerbations of asthma, possibly in relation to GERD. Although GERD is associated with frequent exacerbations of severe asthma,3 there is no clear evidence of benefit in the treatment of GERD in patients with stable asthma or exacerbations of asthma. The study they suggest conducting would be interesting in order to determine whether a causal relationship between GERD and exacerbations of asthma exists, since at present such evidence is lacking.
In answer to Kuramochi and Morita, we chose telithromycin because Sanofi-Aventis was willing to sponsor the study; respiratory pathogens are susceptible to telithromycin, whereas macrolide resistance is widespread; and telithromycin may have less potential to select for resistance than do other antibiotics. We doubt whether the inhibition of theophylline metabolism could explain the mechanism of action, since only seven patients who were treated with telithromycin received this drug, which is largely ineffective in exacerbations of asthma.4
In response to the warning by Osawa and Andraws that the use of telithromycin for exacerbations of asthma should be strongly discouraged, we agree that before any clinical recommendation can be made, further studies are needed to confirm our results and to identify patient populations that may benefit. We also agree that a study in which all patients receive oral corticosteroids would be informative. However, we disagree that the clinical benefit was minimal, since the FEV1 improved twice as much in treated patients as in those receiving placebo, and patients receiving telithromycin had a 50 percent improvement in symptoms three days sooner than did those receiving placebo. We hope our findings will stimulate further study so that clearer clinical guidance regarding the role of ketolides and related antibiotics in the treatment of exacerbations of asthma will become available.
Sebastian L. Johnston, M.D., Ph.D.
National Heart and Lung Institute
London W2 1PG, United Kingdom
Richard B. Nieman, M.D.
Berlex
Wayne, NJ 07470
for the Telithromycin, Chlamydophila, and Asthma Trial Investigators
Since publication of the article, Dr. Johnston reports having received grant support from GlaxoSmithKline and AstraZeneca.
References
FitzGerald JM, Becker A, Sears MR, Mink S, Chung K, Lee J. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004;59:550-556.
Edwards MR, Johnson MW, Johnston SL. Combination therapy: synergistic suppression of virus-induced chemokines in airway epithelial cells. Am J Respir Cell Mol Biol 2006;34:616-624.
ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2005;26:812-818.
Rodrigo C, Rodrigo G. Treatment of acute asthma: lack of therapeutic benefit and increase of the toxicity from aminophylline given in addition to high doses of salbutamol delivered by metered-dose inhaler with a spacer. Chest 1994;106:1071-1076.