This PCR-stratified, double-blind, randomized, controlled trial of clarithromycin or placebo added to fluticasone in patients with suboptimally-controlled persistent asthma demonstrated that there is not a beneficial effect on asthma control of adding clarithromycin to inhaled fluticasone in patients similar to those entered into this trial. The PCR-stratified approach employed herein allowed us to test the effect of clarithromycin on asthma control independently in patients who did and did not have molecular evidence of atypical bacteria in the lower airways. Given full enrollment of the PCR negative stratum, we have robustly demonstrated a lack of effect in those who do not demonstrate PCR evidence of Mycoplasma pneumoniae
or Chlamydophila pneumoniae
on endobronchial biopsy, as well as in the study population as a whole when analyzed independent of PCR status. However, the underenrollment of the PCR positive stratum resulted in inadequate power to robustly test the effect of clarithromycin in the PCR positive subpopulation, leaving the question of efficacy in this group of asthmatics as of yet unanswered. Our findings address an area of uncertainty in asthma pharmacotherapy (9
) and provide evidence that clarithromycin should not be considered as an addition to inhaled corticosteroids to improve disease control in patients with suboptimally-controlled mild-to-moderate persistent asthma who are PCR negative for C. pneumoniae
and M. pneumoniae
, a group that constituted 87% of the participants enrolled in this study and therefore possibly the majority of the adult asthma population as well. Additionally, our results suggest that C. pneumoniae
and M. pneumoniae
serologic evaluation is of minimal clinical utility in this setting, as serology predicted neither PCR status nor response to clarithromycin.
While there was no effect of adding clarithromycin to fluticasone on physiologic measures of airflow or bronchodilator response, there was a clinically- and statistically-significant effect of clarithromycin on airway hyperresponsiveness in PCR negative participants, as indicated by a doubling of the concentration of methacholine required to produce a 20% decline in FEV1
in those allocated to clarithromycin. This occurred despite the fact that all participants were being treated concurrently with fluticasone and suggests that non-antibiotic effects of clarithromycin on airway smooth muscle functional or inflammatory phenotype can be seen even in patients treated with inhaled corticosteroids. The improvement in airway hyperresponsiveness with clarithromycin in asthma patients already receiving inhaled corticosteroids is of interest, augments prior reports from small uncontrolled clinical studies (23
), and supports prior observations that macrolides might modulate this effect through non-antimicrobial pathways including alteration of cholinergic signaling pathways or attenuation of endothelin-1 expression by airway epithelial cells (25
Additionally, while clarithromycin did not have a beneficial effect on exhaled nitric oxide or asthma-specific quality of life, it was weakly associated with a reduction in the need for rescue albuterol use, both in PCR negative subjects and in the population as a whole. Of additional interest (although not definitive) were our findings with regard to the time to achievement of a clinically-significant improvement in asthma control, where those participants who were PCR positive achieved a 0.5-unit improvement in the ACQ more rapidly than did those who were PCR negative. Similarly clarithromycin treatment was associated with a greater likelihood of achieving improvements in the ACQ that exceeded the minimal clinically-important difference. While these results are subject to the limitation of the small sample size in the PCR positive stratum and are secondary outcomes, they raise the possibility that there may be a relevant interaction between PCR status and response to clarithromycin.
The results of this study are likely generalizable to most adults with mild to moderate persistent asthma, although extrapolation to severe disease may not be appropriate given the lack of enrollment of participants with severe asthma into this trial. The PCR negative stratum (which comprised 87% of study participants) of the study was adequately powered to detect an effect of clarithromycin on asthma control and did not. A similar lack of effect was observed in analyses in which all participants (independent of PCR status) were included, indicating a lack of benefit of clarithromycin overall. Additionally, we enrolled adults with asthma that remained suboptimally controlled despite low-dose inhaled corticosteroid monotherapy. This subset of individuals likely comprises a substantial proportion of the asthmatic population (14
), and for them guidelines recommend either increasing the dose of inhaled corticosteroids or adding a second asthma controller medication such as a long-acting beta2
). In this context, our findings indicate that clarithromycin should not be considered as the next therapeutic step in mild and moderate persistent asthmatics. While weak trends were observed toward a favorable effect of clarithromycin on asthma control in PCR positive patients, these findings were not statistically significant and can not be considered conclusive. Thus, while there may be a beneficial effect of clarithromycin in those with evidence of M. pneumoniae
or C. pneumonia
or in other patient populations not included in our study (e.g. those with more severe or neutrophil-predominant asthma (8
)), further research will be required to definitively assess the role of macrolide antibiotics in these subpopulations.
Certain features of the study design should be considered when interpreting these results. Clarithromycin was chosen because, when compared with other macrolides, it is preferentially concentrated in the lung epithelial lining fluid (28
), it may be less likely to contribute to antimicrobial resistance than other members of the macrolide family (30
), its side effect profile with extended treatment period has been described (32
), it is unlikely to significantly alter fluticasone pharmacokinetics (34
), and it has been previously used in asthma (7
). However, it is possible that the antimicrobial or anti-inflammatory effects might have been greater had another member of the macrolide class been chosen. Of note, the absence of a significant improvement in asthma control in both the entire study population and the PCR negative subset suggests that an effect of clarithromycin on glucocorticoid metabolism, similar to that previously described with the macrolide antibiotic troleandomycin (35
), was not present.
Another novel feature of this study is the choice of asthma control, a composite variable which differs from quantitative physiologic or inflammatory parameters, as the primary outcome variable. This outcome measure was chosen for several reasons: it is patient-centered, taking clinical variables such as symptoms and beta-agonist use into account, it is a reliable technique for assessing asthma disease activity and control, and it incorporates a quantitative measure of airflow in the FEV1. It is possible that the use of a composite variable could have obscured the effect of clarithromycin in one or more clinical or physiologic domains, but we did not show a clear benefit of clarithromycin on lung function, and only a weak trend toward a reduction in rescue bronchodilator use was observed.
Complete enrollment of the PCR positive arm of this trial was hampered by a lower-than-anticipated prevalence of PCR positivity for M. pneumoniae
and C. pneumoniae
. A previous study indicated that PCR evidence of these organisms could be found in 56% of adults with asthma, with 30% demonstrating these organisms in the lower airway (2
), whereas in this trial, overall lower airway positivity was 13%. While the reason for this reduced prevalence in our study is not clear, the prior report of Martin and colleagues suggested the possibility of a reduction in the likelihood of PCR positivity in those participants who were using ICS (2
). Since the run-in and treatment periods of this study exposed all participants to a fixed continuous dose of fluticasone, it is possible that this treatment reduced the prevalence of PCR positivity for M. pneumoniae
and C. pneumoniae
in our study population. Given that the technical approaches to obtaining and processing endobronchial biopsies used in this study were similar to those previously employed by investigators in this area (2
), we believe it is unlikely that technical factors alone explain the difference. Whatever the cause, given the fact that the PCR positive group did not have adequate enrollment to robustly test the effect of supplemental clarithromycin in this group, it remains unknown if clarithromycin is of clinical benefit in patients who are PCR positive for either M. pneumoniae
and C. pneumoniae
In conclusion, this study demonstrated that there is not a beneficial effect on asthma control or lung function of adding clarithromycin to fluticasone in adults with persistent, suboptimally-controlled asthma. There was a significant reduction in airway hyperresponsiveness seen with clarithromycin treatment in this study, occurring in the absence of concordant improvements in multiple other clinical and physiologic parameters. While our findings do not support a role for clarithromycin in the treatment of suboptimally-controlled asthma, particularly in those without evidence of mycoplasma or chlamydophila in the lower airway, further studies are warranted to characterize the role of microbial communities in the asthmatic airway (37
) and to determine if evidence of bacterial colonization or infection in the lower airway is predictive of asthma phenotype or clinical improvement with antibiotic treatment.
The “Macrolides in Asthma” trial evaluated if clarithromycin improved control of mild-to-moderate persistent asthma above that achieved with low-dose fluticasone alone. Clarithromycin did not improve asthma control, lung function or quality of life, but did improve airway hyperresponsiveness.
The addition of clarithromycin in adults with mild-to moderate persistent asthma that is suboptimally-controlled by low-dose ICS alone does not further improve asthma control.