Abstract
In addition to direct antibacterial actions, 14- and 15-member-ring macrolides have immune modulating effects that appear to be the reason for clinical benefit in diffuse panbronchiolitis.
A literature search was conducted for studies of the clinical effectiveness of macrolides in other chronic lung conditions.
A number of studies were identified that showed short-term beneficial outcomes or the potential for such outcomes in cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, asthma and post-transplant obliterative bronchiolitis. The studies were limited by small patient numbers, different outcome measures and short-term follow-up, and were not designed to assess potentially harmful effects.
Further large prospective and long-term studies are required in order to identify potential benefit and harm before these agents can be recommended routinely for these conditions.
Macrolide antibiotics are used as first-line agents in the treatment of acute bacterial infections, such as community-acquired pneumonia 1. In addition to direct antimicrobial activity, macrolides also exert immune modifying effects 2, 3. The potential clinical benefit of these properties was first investigated in steroid-dependent asthma 4. In one study, patients concurrently treated with the macrolide troleandomycin were able to significantly reduce their total steroid dose without a significant decrease in asthma control 5. Subsequently, this was shown to be due, at least in part, to alterations in steroid metabolism, with troleandomycin reducing methylprednisolone clearance by 60% 6. Nelson et al. 7, in a 2-yr double-blind placebo-controlled study, showed that the combination of macrolide and methylprednisolone produced no significant clinical benefit in steroid-dependent asthma but, instead, resulted in an increase in steroid-induced side-effects, e.g. accelerated loss of bone density and increased sugar levels.
The chance finding that erythromycin treatment radically improved the clinical outcome of a patient with diffuse panbronchiolitis rekindled interest in the use of macrolides as a potential treatment in other inflammatory airway disorders, e.g. cystic fibrosis 8. Diffuse panbronchiolitis is a progressive inflammatory disorder of lung airways found almost exclusively in Japan. Clinically it is characterised by chronic cough, excessive sputum production, exertional breathlessness, chronic sinusitis and Pseudomonas colonisation 9. Untreated, the prognosis of diffuse panbronchiolitis is poor, with progressive deterioration of lung function, the development of diffuse bronchiectasis and death caused by respiratory failure. The introduction of long-term macrolide therapy has resulted in dramatic improvements in survival, with 5-yr survival rates increasing from 63 to 92% 9, 10. Significant symptom reduction and improved pulmonary function have also been achieved 11–14. The mechanism of action is thought to be due to immune modifying effects rather than direct antimicrobial activity. Clinical improvement has been reported independent of the presence or absence of chronic airway infection 11 and with antibiotic levels below the minimum inhibitory concentrations of several pathogenic bacteria 15.
The anti-inflammatory properties of macrolides are related to structure, with immunomodulatory effects seen with 14- (erythromycin, clarithromycin and roxithromycin) and 15- (azithromycin) but not 16-member (josamycin) macrolides 16. Macrolides are postulated to reduce airway inflammation via several mechanisms. These effects include reduced airway mucus secretion 17 and anti-inflammatory properties, including decreased airway neutrophil accumulation through a reduction in expression of pro-inflammatory cytokines, e.g. interleukin (IL)-8, and adhesion molecule production, e.g. macrophage adhesion molecule-1 18–20. Antipseudomonal activity may also be important 3.
In addition to the potential benefit, use of these agents also has the potential for harm. In addition to many of the usual risks from antimicrobial therapy, macrolides also have clinically significant effects on cardiac conduction 21 and may be important promoters of antimicrobial resistance 22.
The role of macrolides in the treatment of diffuse panbronchiolitis is well established. What is less clear is the evidence for a role of macrolides in the treatment of other chronic inflammatory airway diseases, e.g. cystic fibrosis, bronchiectasis, asthma, obliterative bronchiolitis, chronic obstructive pulmonary disease (COPD) and chronic rhinosinusitis. The possible anti-inflammatory mechanisms of macrolide action have recently been reviewed 3. The aim of the present review was to examine clinical studies regarding macrolide treatment in such inflammatory conditions in order to identify evidence of a significant clinical benefit, and, where possible, to balance this against the potential for harmful effects of these agents.
METHODS
A literature search was conducted using PubMed/MEDLINE. The terms macrolide OR erythromycin OR clarithromycin OR azithromycin OR roxithromycin OR troleandomycin OR telithromycin were used in conjuncture with each condition: asthma, bronchiectasis, cystic fibrosis, panbronchiolitis, obliterative bronchiolitis, chronic rhinitis, chronic obstructive pulmonary disease and COPD. Only double-blind placebo-controlled trials were included in the review of asthma since many more such studies were available.
CLINICAL TRIALS
Cystic fibrosis
A number of clinical trials, including four randomised double-blind placebo-controlled trials comprising 368 patients, have shown evidence of beneficial effects of macrolide treatment in both adults and children with cystic fibrosis (table 1⇓). The largest clinical trial of azithromycin treatment in cystic fibrosis studied 185 patients aged >6 yrs who were chronically infected with Pseudomonas aeruginosa and had a forced expiratory volume in one second (FEV1) of >30% of the predicted value 27. Patients were randomised to receive either azithromycin (250 or 500 mg dependent on body weight) or placebo three times a week for 24 weeks. There was a 4.4% relative improvement in FEV1 in the azithromycin group and a 1.8% decline in the placebo group (p = 0.001). A similar improvement was seen in forced vital capacity (FVC). FEV1 returned to baseline 4 weeks after treatment was discontinued. Patients in the treatment group gained significantly more weight than those in the placebo arm (0.7 kg; 95% confidence interval (CI) 0.1–1.4; p = 0.02) and were less likely to suffer an exacerbation (hazard ratio 0.65; 95% CI 0.44–0.95; p = 0.03). A reduction in exacerbation rate was also seen in patients in the treatment arm who had not shown a significant improvement in FEV1 31. A reduction in hospital days (47%) and days of intravenous antibiotic use (39%) was also reported but did not reach significance. Reported adverse events that were significantly more common in the treatment group included nausea (17% more; p = 0.01), diarrhoea (15% more; p = 0.009) and wheezing (13% more; p = 0.007).
Summary of studies examining the clinical effectiveness of macrolide therapy in cystic fibrosis
The finding of a beneficial effect of azithromycin on pulmonary function has been reported in several smaller studies 26, 28–30. A Cochrane review of macrolide therapy undertaken in 2004 concluded that treatment with azithromycin had a small but significant effect on pulmonary function in patients with cystic fibrosis 23. However, more recent data have suggested that the initial benefit in pulmonary function seen with the commencement of azithromycin treatment may not be maintained over the long term. Clement et al. 25 studied the effect of azithromycin therapy over 12 months in 82 patients with cystic fibrosis, 19 of whom were infected with P. aeruginosa. There was no significant difference in FEV1 between the treatment and control group at the end of the study; although the treatment arm initially showed a significant improvement in FEV1, measurements were similar in both groups by 10 months. However, the number of pulmonary exacerbations, time until the first exacerbation and number of additional courses of antibiotics were significantly reduced in the treatment arm. These findings were independent of Pseudomonas status. A retrospective study by Tramper-Stranders et al. 24 reported that, although significant improvements in FEV1 were measured up to 1 yr after commencement of azithromycin in 100 patients with cystic fibrosis, this improvement was not maintained in the longer term and FEV1 fell in the second and third years of follow-up. This study also reported marked increases in Staphylococcus aureus resistance to macrolides, up to 83% after 1 yr, 97% after 2 yrs and 100% after 3 yrs of azithromycin therapy. Increased macrolide resistance in S. aureus and Haemophilus spp. was also reported by Phaff et al. 32 in a population receiving azithromycin maintenance therapy over a 4-yr period.
There is consistent evidence that macrolide therapy reduces infective exacerbations, decreases the requirement for additional antibiotics and improves nutritional measures in patients with cystic fibrosis. However, short-to-medium term improvements in lung function may not be maintained in the longer term. Whether infective exacerbations are reduced in frequency over the long term and what clinical impact increased macrolide bacterial resistance has requires further study.
Bronchiectasis
The role of macrolide therapy in bronchiectasis treatment has been examined only in five small studies, with a maximum of 39 patients (table 2⇓). Only two were randomised double-blind placebo-controlled trials. Koh et al. 37 showed a significant decrease in airway responsiveness to methacholine in children with bronchiectasis (and increased airway responsiveness) who received roxithromycin (n = 13) for 12 weeks compared to controls (n = 12). There was no change in spirometric results, but, by 6 weeks, significant improvements in sputum purulence scores were observed in the treatment arm. The clinical significance of reduced airway responsiveness in bronchiectasis is unclear. Tsang et al. 36 studied the effect of erythromycin (500 mg twice daily) for 8 weeks on adult subjects with stable severe idiopathic bronchiectasis. A significant improvement in FEV1, FVC and sputum volume was seen in subjects receiving erythromycin (n = 11) compared to controls (n = 10). Measurements of sputum pathogens and pro-inflammatory mediators (IL-8, tumour necrosis factor-α, IL-1α and leukotriene B4) did not change in either group during the study 36.
Summary of studies examining the clinical effectiveness of macrolide therapy in bronchiectasis
A placebo-controlled trial of children with bronchiectasis treated with clarithromycin for 3 months showed no change in FEV1, although maximal mid-expiratory flow (FEF25-75) was significantly improved and there was a significant reduction in sputum volume 33. A reduction in bronchoalveolar lavage (BAL) fluid IL-8 concentration was seen in the treatment arm, but no change in pathogens or other measures of inflammation, including IL-10 and tumour necrosis factor-α, was measured. Cymbaala et al. 34 showed a reduction in sputum volume and infectious exacerbation frequency in adults (n = 11) treated with azithromycin in a randomised crossover study design. A quarter of the study population complained of diarrhoea as a side-effect of azithromycin treatment, with one individual withdrawing from the study. A prospective cohort study of 39 patients with frequent exacerbations of bronchiectasis (more than four exacerbations in 12 months), showed significant improvements in exacerbation frequency, use of intravenous antibiotics, sputum production and symptom scores when subjects received 4 months of azithromycin treatment 35.
The trials of macrolide treatment in bronchiectasis are limited in number, size of study population, and length of treatment and follow up. However, there is consistent evidence of a decrease in exacerbation frequency and sputum volume. These findings would need to be confirmed in much larger studies with longer follow-up times and careful assessment of harmful effects in order to define a role for macrolides in bronchiectasis treatment.
Chronic obstructive pulmonary disease
One published study has examined the effect of clarithromycin treatment in COPD 38. This was a prospective double-blind randomised controlled trial of 67 patients with moderately severe COPD. The effects of 3 months’ clarithromycin therapy on health status, exacerbation rate and sputum bacterial numbers were measured. Overall, no significant benefit was seen in any measure. However, significant improvements in both the St George’s Respiratory Questionnaire symptom score and 36-item short-form health survey physical function score were seen.
Wilkinson et al. 39 recently presented results of a similarly designed study in abstract form. This study measured the number of treated exacerbations as a primary outcome in 109 patients with COPD treated with erythromycin for 1 yr. Patients in the placebo arm were significantly more likely to be treated for an exacerbation than subjects treated with erythromycin (odds ratio 1.48; p = 0.004). The number of studies investigating macrolide therapy in COPD is clearly extremely limited (table 3⇓), but the positive benefit seen in the most recent study suggests that more work should be undertaken.
Summary of studies examining the clinical effectiveness of macrolide therapy in chronic obstructive pulmonary disease
Chronic rhinosinusitis
Macrolide treatment of chronic rhinosinusitis has been investigated in several open-label studies 40–42. For example, a prospective open-label study of 17 patients with persistent sinusitis following sinus surgery, using erythromycin treatment, showed significant improvements in saccharin transit time and symptoms, including nasal congestion, rhinitis and headache, at 3 and 12 months of follow-up 41. The first double-blind randomised placebo-controlled study examining the effects of low-dose macrolide therapy in chronic rhinosinusitis was reported in 2006 43. This study investigated the effects of 3 months’ roxithromycin treatment in 64 patients with chronic rhinosinusitis. Significant improvements were measured in rhinosinusitis-specific quality-of-life scores (20-item Sino-Nasal Outcome Test (SNOT-20)), saccharin transit time, nasal endoscopic scoring and nasal lavage levels of IL-8. Outcomes were better in patients with low immunoglobulin E levels. A further SNOT-20 assessment was then carried out 3 months after cessation of macrolide therapy, and improvements in scores were not maintained. The results from this study are encouraging but further work is required in order to define a role for macrolide therapy in the treatment of chronic rhinosinusitis.
Asthma
Several randomised double-blind placebo-controlled trials have examined the role of macrolide therapy in the management of chronic asthma (table 4⇓). Proposed mechanisms of macrolide action in asthma include direct antimicrobial activity, alteration of steroid metabolism and anti-inflammatory effects 47. Early studies of troleandomycin in oral steroid-dependent asthmatics suggested a significant steroid-sparing role. For example, an open-label study of Zeiger et al. 5 showed significant symptom and spirometric improvements along with a reduction in steroid dose. A small study of Kamada et al. 52, of 18 severe steroid-dependent asthmatic children, showed a significant decrease in oral steroid requirement in the troleandomycin and methylprednisolone group compared to placebo; however, no improvement in FEV1 was seen. Troleandomycin reduces methylprednisolone clearance; this mechanism is thought to be a factor in the reduced steroid requirement in these patients 6. However, a double-blind placebo-controlled trial of troleandomycin added to methylprednisolone in 75 steroid-dependent asthmatics over a 2-yr period showed no benefit in reducing steroid dose to control asthma symptoms 7. However, there was a significant reduction in bone density in the macrolide group.
Summary of randomised-controlled studies examining the clinical effectiveness of macrolide therapy in asthma
Chronic infection with atypical organisms may play a role in the pathogenesis or severity of chronic asthma 53, 54. Two studies have examined the effects of macrolide therapy in asthmatics with serological or PCR evidence of infection with Mycoplasma pneumoniae or Chlamydia pneumoniae. The largest study of Black et al. 49 examined the effect of 6 weeks’ roxithromycin or placebo treatment on 232 asthmatics with serological evidence of infection with C. pneumoniae. No significant change in the primary end-points of mean morning peak expiratory flow (PEF) or symptom score was observed. There was a significant improvement in evening PEF by 6 weeks, but this was nonsignificant after 6 months’ follow-up 49. This was in direct contrast to a smaller study of Kraft et al. 48, who measured significant improvements in FEV1 only in asthmatics whose BAL fluid was PCR-positive for either M. pneumoniae or C. pneumoniae compared to PCR-negative subjects.
The lack of a gold standard for proof of C. pneumoniae infection may be one reason for the inconsistent findings. The use of serology, by Black et al. 49, to define infected and noninfected populations may have resulted in a dilution of subjects with true chronic infection with those previously exposed but not currently infected. By contrast, Kraft et al. 48 used PCR to define their populations and probably had a higher chance of delineating between truly infected and noninfected individuals. A further confounding factor may have been differences in numbers treated with inhaled corticosteroid (30% of subjects in the study of Kraft et al. 48 compared to >75% in the study of Black et al. 49).
Two studies have shown significant reductions in bronchial hyperresponsiveness in patients with asthma after 8 weeks’ treatment with clarithromycin; neither showed any significant change in FEV1 47, 50. The first study examined 17 patients with allergy-induced asthma and demonstrated a significant reduction in blood and sputum eosinophil counts, suggesting a possible anti-inflammatory role for clarithromycin 50. Patients taking oral or inhaled corticosteroid were excluded. The second study examined asthmatics taking 800 μg budesonide daily; serum-free cortisol levels showed no change from baseline levels after treatment with clarithromycin, suggesting that altered steroid metabolism was not the effect mechanism 47. Evidence for reduced bronchial hyperresponsiveness has also been demonstrated after treatment with erythromycin, roxithromycin and azithromycin 55–57. A more recent study of Simpson et al. 45 showed improvements in quality-of-life scores and significant reductions in wheezing in patients with refractory asthma. No improvement in bronchial hyperresponsiveness or FEV1 was seen. Improvement in quality-of-life scores was matched by significant reductions in induced sputum neutrophil numbers and IL-8 and neutrophil elastase levels. The authors reported that improvements in quality of life and measures of inflammation were most apparent in non-eosinophilic asthmatics.
Interpretation of the studies as a whole is difficult because of the heterogeneous nature of the study populations, the small number of patients studied and the short study durations (≤12 weeks). This was reflected in the conclusion of a Cochrane review of Richeldi et al. 44, which stated there was insufficient evidence to support or refute the use of macrolides in the management of chronic asthma.
A recent study of Johnston et al. 46 examined the effect of the ketolide telithromycin on the management of acute exacerbations of asthma. This was a double-blind placebo-controlled study of 278 adults who were randomised to receive 10 days of either oral telithromycin or placebo. The primary outcomes were change from baseline asthma symptoms and home-recorded morning PEF. Patients in the treatment arm showed a significant reduction in asthma symptoms compared to placebo (p = 0.004), but no difference in home-recorded PEF was seen. Significant improvements in symptom-free days (16 versus 8%; p = 0.006) and other measures of pulmonary function were seen in the treatment arm when measured in the clinic at the end of treatment but not at a 6-week follow-up (including FEV1, PEF, FVC and FEF25–75). There was evidence of C. pneumoniae or M. pneumoniae infection in 61% of the study population; however, bacteriological status was not related to telithromycin response. Nausea was reported significantly more frequently in the telithromycin group (p = 0.01), and elevation of liver enzyme levels was seen in two patients in the telithromycin group who had shown abnormal enzyme levels prior to commencement of treatment. This study shows some benefit with ketolide treatment in acute asthma; the high apparent prevalence of C. pneumoniae or M. pneumoniae suggests that the mechanism of action may be related to direct antimicrobial activity. It is unclear whether the benefit measured translates into a clinical benefit, and more studies are clearly required.
Post-transplant obliterative bronchiolitis
Bronchiolitis obliterans is a significant cause of long-term morbidity and mortality in patients following lung transplantation. Bronchiolitis obliterans syndrome (BOS) is the clinical manifestation of chronic airways rejection 58. A progressive decline in FEV1 is often seen, and mortality rates of 25–50% have been reported 59, 60. Several small studies (maximum 20 patients) have examined the potential benefit of azithromycin in the treatment of post-transplant obliterative bronchiolitis (table 5⇓). Five prospective open-label studies have been undertaken, with four showing significant improvements in FEV1 with azithromycin treatment 61, 62, 65, 66 and one showing no significant effect 63. One retrospective study also showed a significant increase in FEV1 with azithromycin treatment 64. The largest prospective study treated 14 patients with azithromycin three times weekly for 12 weeks 66. A 13% increase in FEV1 was seen in the group as a whole, an increase of 0.31 L (p = 0.007). Only six out of the 14 study subjects showed an improvement in FEV1 of >10%. All of the subjects underwent BAL prior to and after 3 months of treatment. Absolute BAL fluid neutrophil count, the proportion of neutrophils, and levels of IL-8 and -17 were significantly reduced in the patients with significant changes in FEV1 but not in the eight subjects who had shown no response. The authors stated that a BAL fluid neutrophilia of >15% predicted a significant response to azithromycin treatment (positive predictive value 85%). There was no difference in colonisation with Pseudomonas between the groups.
Summary of studies examining the clinical effectiveness of macrolide therapy in post-transplant obliterative bronchiolitis
Two studies have examined the possible role of C. pneumoniae infection in the development of BOS after lung transplantation. Kotsimbos et al. 67 showed that a mismatch in donor–recipient C. pneumoniae serology (i.e. donor positive/recipient negative) was an independent risk factor for the development of BOS. With the reverse mismatch (i.e. donor negative/recipient positive) the risk of BOS was reduced. Glanville et al. 68 showed that C. pneumoniae infection in lung transplants was associated with a worse outcome and increased risk of BOS. One mechanism by which macrolide therapy may benefit lung transplant patients could be in the treatment of C. pneumoniae infection, but this issue remains bedevilled by the lack of a gold standard for this infection, as indicated earlier.
Other
Ballard et al. 69 conducted a study of azithromycin in extremely low birthweight babies to assess its impact on the incidence and severity of bronchopulmonary dysplasia. This was a double-blind randomised placebo-controlled trial of neonates admitted to an intensive care unit to receive mechanical ventilation. No difference in mortality, incidence of bronchopulmonary dysplasia, duration of mechanical ventilation or other morbid conditions was seen. Post-natal steroid use in the whole study population and duration of ventilation in survivors was significantly less in the treatment group.
DISCUSSION
The dramatic improvement in the mortality and morbidity of diffuse panbronchiolitis with the introduction of macrolide therapy has increased interest in the potential use of macrolides in the treatment of other chronic inflammatory airway conditions. The aim of the present review was to examine the current evidence for a role of long-term macrolide therapy in the clinical management of these chronic diseases.
The use of azithromycin in cystic fibrosis has shown short-term improvements in pulmonary function (FEV1), although more recent data suggest that this improvement is not maintained in the long term. However, there is some evidence for a reduction in exacerbation rate, decreased additional antibiotic usage and improvements in nutritional measures. How these potential benefits compare to the risks of increased bacterial resistance and whether clinical benefit is maintained over the long term requires further evaluation.
In the treatment of bronchiectasis with macrolides, studies show consistent evidence of decreased sputum volume and two studies also show decreased exacerbation frequency. The studies are very limited in terms of size, duration of follow-up and design. Larger studies of longer duration are required. The number of studies in COPD is even fewer. However, the positive finding of decreased exacerbation frequency, recently reported by Wilkinson et al. 39, suggests that further work in this area may be warranted. Two clinical trials examining the effects of azithromycin therapy on lung function and time to first exacerbation in COPD patients are currently under way; both are large studies with >800 and >1,000 patients, respectively (registered at ClinicalTrials.gov (trial numbers NCT00325897 and NCT00132860) ). Data from these trials may help in determining whether or not long-term macrolide therapy has a role in the treatment of COPD.
There is currently no clear evidence that the use of macrolides in the treatment of chronic asthma results in significant clinical benefits. The use of the ketolide antibiotic telithromycin in the treatment of acute exacerbations of asthma showed significant improvements in symptom scores and laboratory-measured pulmonary function test results. However, it is not clear whether this translates into a significant clinical benefit and more studies are, therefore, required. Findings from open-label studies of macrolide therapy in post-transplant obliterative bronchiolitis are promising but require validation in long-term double-blind randomised placebo-controlled trials prior to routine use of this treatment. The role of C. pneumoniae infection also needs to be further investigated.
In all of the above studies, assessment of macrolide impact is confused by the heterogeneous nature of both study populations and outcome measures, both beneficial and harmful. Spirometric measures of lung function as a primary outcome may not be the best indicator of the benefits of macrolide therapy. Clinically relevant end-points, such as reductions in exacerbation frequency, requirement for additional antibiotics, hospital stays, improved nutritional measures, symptom scores and quality-of-life assessments, should be the goal of future studies.
With very few exceptions, the studies identified were not designed to explore the potential for significant side-effects caused by the prolonged use of macrolides. The potential benefits need to be balanced against the risks, to both the individual and the population as a whole, of introduction of these new treatments. Increased bacterial macrolide resistance in common respiratory pathogens is increasing in Europe 70, 71. In the UK, although penicillin resistance in Streptococcus pneumoniae may be declining, macrolide resistance continues to slowly increase 72. This may lead to clinical failure in acute infection 73. Macrolide use is the most important driver of macrolide resistance, with azithromycin selecting quantitatively more resistant organisms and clarithromycin selecting a higher-resistance-coding gene mutation 22. The risk of macrolide resistance in nontuberculous mycobacteria that may be prevalent in cystic fibrosis populations should also be explored 74. Long-term use of macrolides in a rare condition, such as diffuse panbronchiolitis, may generate resistant bacteria in the individual without causing significant harm to the population at large. Their use for much more common conditions, such as asthma and COPD, may have an impact on macrolide resistance in bacteria in the general population. This needs to be explored by further research.
Macrolides possess the potential to have significant electrophysiological effects on the heart, including prolonged cardiac repolarisation (QT prolongation) 75, with resultant proarrhythmogenic effects 76, 77 leading to potentially fatal ventricular tachycardias (torsades de pointes) 78. Ray et al. 76 reported that the use of erythromycin was associated with a doubling in the risk of sudden cardiac death. The risk increased five-fold if patients were concurrently taking drugs that inhibit cytochrome P450 3A, e.g. selective serotonin reuptake inhibitor antidepressants, calcium channel antagonists, amiodarone, certain antiretroviral drugs and various others. It is also possible that this effect is under-reported since sudden death in patients with chronic respiratory diseases may well be assigned to the underlying respiratory condition as opposed to a cardiac arrhythmia. The risk related to a short course of macrolide for an acute infection in a young person might, therefore, be different to that related to prolonged use in an older patient with COPD or bronchiectasis, who is more likely to both have structural cardiac disease and be taking other commonly used drugs that prolong the QT interval 79. Other drug interactions may also be important. For example, the increased risk of statin-induced myopathy reported with concurrent erythromycin or clarithromycin therapy 80, 81.
If macrolides are to be used for their anti-inflammatory effects, which macrolide is preferable? Comparative studies of the relative clinical efficacy of macrolide therapy have not yet been performed. Choice may be determined as much by potential harm as benefit. The use of newer macrolides, e.g. azithromycin, may be associated with a reduced risk of cardiac arrhythmias than use of older macrolides, e.g. erythromycin and clarithromycin 82–84, and may, therefore, be the drug of choice. However, there are case reports of QT prolongation and cardiac arrest with azithromycin 85, 86. However the potential for resistance development may be greater 22.
Macrolides provide an exciting potential new approach to the management of a number of diverse chronic inflammatory lung conditions. The possible beneficial effect across a number of diverse lung conditions is intriguing and perhaps comparable to the effects across a range of diseases found with corticosteroid therapy. This may relate to an as yet undescribed impact on a fundamental intracellular signalling pathway or possibly relates to a combination of factors, e.g. immune-modulatory and antimicrobial properties including antipseudomonal activity.
Initial studies show promise, but this promise has yet to be realised. The temptation for premature clinical use should be resisted as there is an as yet unquantified risk of harm. Further large controlled trials in these conditions, carefully measuring both benefit and harm, are required before they become established as part of routine therapy. In the long term, if the benefits are proven, the identification of the precise mechanisms of anti-inflammatory action of these molecules may lead to the synthesis of immunolides, anti-inflammatory macrolides without the potential for antibacterial effect, resistance generation or cardiac side-effects 85, which might then be ideal therapies for these chronic inflammatory airway diseases.
Statement of interest
A statement of interest for M.A. Woodhead can be found at www.erj.ersjournals.com/misc/statements.shtml
- Received March 19, 2008.
- Accepted August 21, 2008.
- © ERS Journals Ltd
References
