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Reviving an old class of antimicrobials – but not for their antimicrobial properties
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The macrolide antibiotics have been around since 1952. Erythromycin A was the first of the class to be marketed and used as an alternative to beta lactam agents for the treatment of gram-positive infections.
The class was soon expanded with the development of clarithromycin (Biaxin), azithromycin (Zithromax) and telithromycin (Ketek). The “macrolide” family is a collection of a distinct compounds with a large macrolactam rings. The antibiotics consist of 14-, 15- and 16- member macrolactam rings. Clarithromycin is the most similar to erythromycin with a 14- membered ring. Azithromycin is a 15-membered ring and telithromycin has a 16-membered ring. The agents work by inhibiting RNA-dependent protein synthesis by reversibly binding the 50S ribosomal subunit of susceptible organisms.
Clarithromycin, azithromycin and telithromycin have a broader spectrum of activity than erythromycin. All agents have gram positive activity against erythromycin-sensitive Streptococcus pneumoniae, Staphylococcus aureus (except for methicillin-resistant S. aureus), and Group A, B, C, and G streptococcus. These agents also cover Haemophilus spp., Moraxella catarrhalis, and atypical pneumonia pathogens, including Legionella pneumophila, Chlamydia pneumoniae and Mycoplasma pneumoniae. The newer macrolides have enhanced gram-negative activity against Escherichia coli, Salmonella spp., Yersinia enterocolitica, Shigella spp., Campylobacter jejuni, Vibrio cholerae, Neisseria gonorrhoeae and Helicobacter pylori. The primary use of each of these agents is for community acquired respiratory tract infections.
Non-antibacterial properties
So why discuss these otherwise old, well-defined agents?
A growing interest in the macrolides’ non-antibacterial properties has come to the forefront in the last several years. A new accumulation of evidence has suggested that these agents are potent immunomodulators and have well described in vitro anti-inflammatory properties. It is suggested that these agents could be beneficial for chronic inflammatory airway diseases such as asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis. Some studies are ongoing for other chronic inflammatory diseases such as chronic sinusitis and pyelonephritis with suggested clinical benefit from macrolide use not related to their antibacterial properties. The most recent evidence studied the benefits of clarithromycin in septic patients related to ventilator associated pneumonia (VAP). This immunomodulatory/anti-inflammatory features is not a “new” concept per se.
Diffuse panbronchiolitis
The macrolides have been used to treat diffuse panbronchiolitis (DPB) since 1982. DPB is a chronic, progressive, obstructive syndrome that affects the upper and lower airways. It is characterized by the infiltration of the bronchial wall by lymphocytes and plasma cells with peribronchiolar distinctive foamy macrophages. DPB solely presents in Eastern Asian populations. The macrolides were first endorsed as standard of treatment for DPB in Japan in 1982. Another disease state similar to DPB is cystic fibrosis (CF). These two conditions share many clinical features. In CF, neutrophils are the predominate inflammatory cells which result in the airway destruction secondary to neutrophil-derived proteases and oxidants. In both groups, the patients are often infected with mucoid strains of Pseudomonas aeruginosa and mortality is attributed to chronic progressive lung disease. Many treatment strategies, antibacterial and non-antibacterial, have been employed to for treatment of these disease states. The macrolides have become standard of treatment for DBP and CF and have sparked a new interest for clinicians for the treatment of other chronic airway diseases.
A clear role of the macrolides in the treatment of DPB has been established. One of the largest, most noteworthy studies of this issue was conducted by Rubin et al. This study examined 498 Japanese patients with DPB; the results showed significant improvement in survival when patients were treated with 400 mg to 600 mg daily of erythromycin. The patients were divided into three groups: Group A consisted of those receiving the diagnosis of DPB from 1970 to 1979 (n=190); Group B was those receiving the diagnosis from 1980 to 1984 (n=221); Group C was those receiving the diagnosis from 1985 to 1990 (n=63).
Group A was the historical control. The patients were evaluated by comparison of Kaplan-Meier survival curve. Group C (n=63) who had been treated with erythromycin compared to group A and B showed significant improvement in survival (P< 0.0001).
Many other small studies in DPB patients have shown long-term efficacy and safety, improvement in FEV1, FVC, resting PaO2, baseline positive cultures becoming negative, decreased number of neutrophils and concentrations of interleukin (IL-8) in bronchial alveolar lavage fluid. While many mechanisms by which macrolides improve DPB have been hypothesized, the most clear is inhibition of pulmonary influx of neutrophils. In most chronic inflammation of the airways, airways secrete elastase, myeloperoxidase and inflammatory mediators that in turn cause epithelial dysfunction. Macrolides are thought to inhibit many of these processes and reduce accumulation of neutrophils in the airway causing less destruction. There is also in vitro data to suggest macrolides protect the epithelium and improve the movement of airway secretions.
Benefits for CF patients
A handful of evidence in CF patients has shown benefit in this population. A combination of treatment strategies including antibiotics, mucolytics and anti-inflammatory agents are needed to effectively treat CF patients. One of the largest, multi-center, double-blind, placebo controlled trials, conducted by Saiman et al, studied CF patients chronically infected with Pseudomonas aeruginosa and placed in azithromycin therapy. The researchers evaluated and measured change in FEV1 from day 0 to completion of therapy at day 168. They also evaluated safety of long term therapy. The secondary outcomes were pulmonary exacerbations and weight gain. The active group received 250 or 500 mg three days a week of azithromycin (dose decided by weight) versus placebo.
The azithromycin group had a mean increase in FEV1 at day 168 (P= 0.009), FVC at day 168 (P= 0.01), less risk of experiencing an exacerbation than placebo (P= 0.03) and weight gain improved by an average of 0.7 kg in treatment group (P=0.02). Adverse effects were mild to moderate in occurrence and consisted of nausea, diarrhea and wheezing. Quality of life was also assessed and the participants in the azithromycin group reported improvements in physical function. For inflammatory markers mean elastase levels and IL-8 levels were evaluated. Mean elastase increased significantly but IL-8 did not change.
Newer macrolides
The newer macrolides, clarithromycin and azithromycin, are considered first-line for treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute bacterial sinusitis and streptococcal pharyngitis.
On the other hand, the role of macrolides for other chronic inflammatory disease (sinusitis, asthma and COPD) has not been well established. Several mechanisms and benefits have been alluded to for respiratory diseases with chronic inflammation. These mechanisms include attenuation of inflammatory responses in the lung, mucoregulatroy properties and effects on bronchial responsiveness.
In asthma, macrolides have historically been selected for their steroid-sparing effects. Clinical studies of corticosteroid-dependent patients with asthma have shown improvement in clinical symptoms thought due primarily to inhibition of steroid metabolism. Studies conducted with troleandomycin, erythromycin and clarithromycin have shown either reduction in steroid use by more than 50%, airway hyperresponsiveness, decrease in hospital admission and improvements in FEV1 and FVC. As for COPD, preliminary data with clarithromycin has been mixed and conclusions for clinical benefit in this patient population cannot be made.
Non-antibiotic effect
The most recent evaluation for the macrolide’s non-antibiotic effect was studied in 200 patients with sepsis and ventilator associated pneumonia (VAP) by Giamarellos-Bourboulis et al. Clarithromycin has shown prolonged survival in experimental models for sepsis. Giamarellos-Bourboulis and colleagues studied the efficacy of clarithromycin 1 gm IV daily for three days on the outcomes of resolution of VAP, duration of mechanical ventilation, and sepsis-related mortality at 28 days. This was a prospective, double-blind, randomized, placebo-controlled, multi-center trial. Patients included were those requiring intubation and mechanical ventilation for more than 48 hours, new/persistent consolidation on lung radiograph, purulent tracheobronchial secretions, clinical pulmonary infection score (CPIS), signs of sepsis, severe sepsis or septic shock. Reasons for intubation varied but approximately 44% of the patients were intubated due to COPD. One hundred and forty-one surviving patients were evaluated.
The resolution of VAP in the placebo group was 15.5 days compared with 10 days in the clarithromycin group. The cumulative incidence of the resolution of VAP revealed that the only parameter that effected baseline function was administration of clarithromycin (P= 0.048). The effect of clarithromycin on mortality was not statistically significant between the two groups but time to death was prolonged in the clarithromycin treated group. CPIS scores improved by days five and 10 (P= 0.016 and P= 0.032, respectively). There are several limitations to this study and the beneficial effect of clarithromycin in sepsis can still only be hypothesized. The dose, route and duration of clarithromycin therapy is an unusual choice, the study did not describe other interventions for the improvement of VAP which could directly impact outcomes and a measurement for direct immunomodulatory/anti-inflammatory effects were not obtained. Even so, the results from this study are encouraging for further research for macrolides in sepsis.
These macrolide antibiotics have been in our arsenal for treatment of different disease states and a variety of organisms for many years. The immunomodulatory and anti-inflammatory properties have been known for many decades in the treatment of diffuse panbronchiolitis and those similar principles have been applied to the cystic fibrosis population. The effects outside of the antibacterial properties of the macrolides are intriguing. Clinicians may be tempted to extrapolate the experiences from the DPB and CF populations to apply to other chronic inflammatory disease states. More conclusive data around these agents use must be further studied. Dosages, regimens, safety, adverse effects of prolonged treatment, evaluation of effect on resistance and clinical outcomes need to be better established. With that said, it is not yet a full revival of the macrolides but a start to re-investigate an older, sometimes forgotten class.
For more information:
- Kimberly Boeser, PharmD, is the infectious disease clinical pharmacologist at the University of Minnesota Medical Center, Fairview in Minneapolis, where she coordinates the antimicrobial stewardship program. Rubin BK and Henke MO. Immunomodulatory activity and effectiveness of macrolides in chronic airway disease. CHEST 2004;125:70-78.
- Saiman L, Marshall BC, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: A randomized controlled trial. JAMA. 2003;290(13):1749-1756.
- Giamarellos-Bourboulis et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. CID. 2008;46;1157-1164.