REVIEWMacrolides and airway inflammation in children
Section snippets
INTRODUCTION
Macrolides have been used as effective bacteriostatic antibiotics since erythromycin (EM) was first marketed in 1952.1 Macrolides inhibit RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal subunit of a susceptible microorganism. Clarithromycin (CAM), roxithromycin (RXM) and the 15-member azalide, azithromycin (AZM) were introduced during the 1980s and early 1990s and have an increased spectrum of activity, can be taken less frequently and have fewer gastrointestinal
MACROLIDE ANTIBIOTICS
As a class, macrolides can have monolactone ring sizes ranging from 8 to 42, as well as 44-, 48- and 62-membered rings.8 Macrolide antibiotics have lactone rings that contain 14-members (EM, RXM, CAM, dirithromycin and TAO), 15-members (AZM), or 16-members (spiramycin, josamycin and midecamycin). A new group of 14-membered macrolide antibiotics known as the ketolides have a 3-keto in place of the L-cladinose moiety.
CAM and AZM are more commonly used in clinical practice because there are fewer
MACROLIDE ADVERSE EFFECTS
When used as an antibiotic, EM activates the motilin receptor and this can cause uncoordinated peristalsis with a 20–25% incidence of anorexia, nausea, or vomiting and an 8% incidence diarrhoea.11 CAM, RXM and AZM have less motilin binding and fewer gastrointestinal adverse effects than EM. Hypersensitivity, headache, hepatoxicity, nephrotoxicity and ototoxicity have been less commonly reported. The macrolides have been shown to potentiate the effects of some drugs by interfering with
IMMUNOMODULATORY EFFECTS
Immunomodulation has been defined as suppressing hyperimmunity and inflammation without overt immunosuppression. The non-ribosomal effects of macrolides include immunomodulation, decreasing bacterial virulence and biofilm formation and decreasing mucus hypersecretion (Fig. 1). These effects are unrelated to antimicrobial effects, take several weeks to manifest and are limited to the 14 and 15 member macrolides. They are not significantly present in the 16 member macrolide antibiotics.12
EFFECTS ON AIRWAY MUCUS
The production of mucus and its clearance by mucociliary transport are a primary airway defence. Chronic inflammation can induce goblet cell and submucosal gland hyperplasia and hypertrophy causing mucus hypersecretion. In 1990, studies suggested that EM can inhibit mucus glycoconjugate secretion from human airway cells in culture.13 In a clinical trial, CAM decreased the volume of expectorated sputum in subjects with chronic bronchitis, bronchiectasis and DPB by a mean of 53%, increased solid
NON-RIBOSOMAL EFFECTS ON BACTERIA
Gram negative bacteria such as Pseudomonas aeruginosa can form biofilms that are protected from phagocytosis and antimicrobial agents. Macrolide antibiotics may attenuate inflammation by reducing bacterial adherence, reducing biofilm formation and inhibiting P. aeruginosa virulence factors.
At sub-MIC90 concentrations, CAM decreased the number of viable bacteria in mice with biofilm-producing P. aeruginosa chronic respiratory infection.18 Macrolides may also reduce biofilm formation by
Inflammatory cells
Inflammatory cells such as neutrophils (polymorphonuclear leukocytes (PMN)) translocate from the bloodstream to the airway via adhesion molecules and release lysosomal enzymes and reactive oxygen species that damage the airway cells. In vitro studies have shown that EM is an alternative substrate inhibitor of human neutrophil elastase (HNE) activity, while flurythromycin (a 14-membered 8-fluoro-macrolide) irreversibly inactivated HNE.28 EM inhibits production of superoxide anion (O2-) in
CYTOKINE, CHEMOKINE AND CHEMICAL MEDIATORS
Long term macrolide therapy appears to suppress pro-inflammatory cytokines, chemokines and chemical mediators that play an important role in initiating inflammation. EM decreased bronchoalveolar lavage fluid (BALF) interleukin (IL)-1β and IL-8 in patients with DPB.36 In vitro, EM and CAM suppressed IL-8 mRNA expression and protein in human normal (NHBE) and transformed bronchial epithelial cells.37 EM significantly suppressed eotaxin protein and mRNA in human lung fibroblasts.38 Macrolides
HOST DEFENCE
In contradistinction to the long-term suppression of increased or hyper-inflammation, macrolides may acutely enhance host defence by the production of inflammatory mediators.48 In healthy subjects, EM increased IL-1 secretion by macrophages from 1.3 ± 0.2 to 3.4 ± 0.5 U × 10−3/culture and IL-2 by splenocytes from 1.36 ± 0.56 to 4.47 ± 1.34 U/ml. RXM also increased IL-1 secretion by macrophages and IL-2 by lymphoid cells.49, 50 EM enhances constitutive nitric oxide synthase (cNOS)-mediated nitric oxide (NO)
Cystic fibrosis
EM was first used for CF therapy in 1991 in a 16 year old Japanese student with severe CF lung disease.5 After treatment with oral EM 600 mg daily for 12 months, sputum production decreased from 70 to 10 ml/day and there was resolution of reticulonodular densities on his chest radiograph. The first Western study of macrolides in CF was reported by the Royal Brompton Hospital in 1998.52 Seven children with a median age of 12.1 years, all of whom were infected with P aeruginosa, received AZM over 3
SINOBRONCHIAL SYNDROME
Vestbo and colleagues showed that adults with chronic obstructive pulmonary disease (COPD) who had mucus hypersecretion also had an excessive decline in pulmonary function and increased risk of hospitalisation.58 CAM can reduce mucus hypersecretion in patients with chronic bronchitis and it is widely used for this indication in Japan.59 After CAM therapy in sinusitis, nasal secretion volume is also significantly decreased.60 In subjects with chronic lower respiratory tract infections given RXM
ASTHMA
Troleandomycin (TAO) was first used as a ‘steroid-sparing’ agent in patients with severe steroid-dependent asthma in 1959 but its use was limited due to severe side effects including cholestasis.66, 67 More recently, Garey and colleagues conducted a placebo-controlled trial of CAM 500 mg twice daily in 21 adults with steroid-dependent asthma.68 Over the course of 6 weeks subjects on CAM had better pulmonary function and fewer symptoms with no increase in the need for oral corticosteroid therapy.
PLASTIC BRONCHITIS
Cast or plastic bronchitis is an unusual disorder that is rarely encountered in children. It is characterised by the expectoration of large branching plugs of airway debris. These ‘casts’ conform to the shape of portions of the tracheobronchial tree and give the disorder its name. Cast bronchitis is typically seen in association with severe asthma (particularly in association with Aspergillosis) and cyanotic congenital heart disease, but plastic bronchitis can also occur as a primary airway
MACROLIDE RESISTANCE
Chronic, widespread, low-dose macrolide therapy is likely to induce antimicrobial resistance among susceptible gram positive organisms. Macrolide antimicrobial resistance comes in two main forms.74 Ribosomal resistance mediated by the ermB gene, produces a higher level of resistance than efflux pump resistance mediated by the mefA gene, which can be overcome by increasing the dosage of medication. Up to 50% resistance in Streptococcus pneumoniae has been reported in Europe and 10–30% resistance
PRACTICE POINTS
- •
Low-dose, long-term macrolide therapy is now recommended for the therapy of cystic fibrosis (CF) and sinobronchial syndrome in children.
- •
Macrolide antibiotics may be effective against Gram negative biofilm producing organisms when given over longer periods and these antimicrobials may disrupt biofilms increasing the effectiveness of co-administered antibiotics.
- •
Side effects of long term low dose macrolide therapy are minimal and gastrointestinal side effects can be minimised by using azithromycin
RESEARCH DIRECTIONS
- •
Clinical trials should focus on assessing which groups of patients are most likely to respond to macrolide therapy as well as on the optimal dosage and duration of therapy.
- •
There are many effects on the inflammatory cascade that have been reported although the underlying mechanisms for these effects still need to be determined.
- •
More potent immunomodulatory macrolides need to be developed without the antimicrobial properties that might induce bacterial resistance to this class of antibiotics.
Acknowledgments
The authors thank Lauren Clarkson and Samir A. Shah for editorial assistance.
References (78)
- et al.
Erythromycin. A microbial and clinical perspective after 30 years of clinical use
Mayo Clin Proc
(1985) - et al.
The use of macrolide antibiotic substances in the treatment of asthma
J Allergy
(1970) - et al.
Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial
Lancet
(2002) - et al.
Influence of macrolides on guanosine diphospho-D-mannose dehydrogenase activity in Pseudomonas biofilm
J Infect Chemother
(2000) - et al.
Effects of subinhibitory concentrations of macrolide antibiotics on Pseudomonas aeruginosa
Chest
(2004) - et al.
Potential of macrolide antibiotics to inhibit protein synthesis of Pseudomonas aeruginosa: suppression of virulence factors and stress response
J Infect Chemother
(2000) - et al.
Roxithromycin promotes lymphocyte apoptosis in Dermatophagoides-sensitive asthma patients
Eur J Pharmacol
(2003) - et al.
Erythromycin inhibits beta2-integrins (CD11b/CD18) expression, interleukin-8 release and intracellular oxidative metabolism in neutrophils
Respir Med
(2000) - et al.
Modulation of Th2 type cytokine production from human peripheral blood leukocytes by a macrolide antibiotic, roxithromycin, in vitro
Int Immunopharmacol
(2001) - et al.
Influences of roxithromycin on cell-mediated immune responses
Life Sci
(1992)