Paediatric Respiratory Reviews
Volume 6, Issue 3 , Pages 227-235, September 2005

Macrolides and airway inflammation in children

Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1081 USA

Article Outline

Summary 

For more than 20 years macrolide antibiotics have been used to treat chronic inflammatory airway diseases based on their immunomodulatory activity. Macrolide antibiotics down-regulate damaging prolonged inflammation as well as increase mucus clearance, decrease bacterial virulence and prevent biofilm formation. Initially shown to decrease morbidity and mortality in diffuse panbronchiolitis and in steroid-dependent asthma, long-term macrolide therapy has now been shown to significantly reduce exacerbations and improve lung function and quality of life in children with cystic fibrosis. They have also proven beneficial in Japanese children and adults with chronic sinobronchitis especially when there is nasal polyposis. Long-term macrolides have also proven clinically beneficial in some patients with plastic bronchitis. Adverse reactions are few and generally self-limited when used at the recommended dosage for immunomodulation.

Keywords: Macrolide antibiotics, Cystic fibrosis, Sinobronchial syndrome, Mucus, IL-8, Plastic bronchitis, Nasal polyposis

 

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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 adverse effects.

Troleandomycin (TAO), a 14-member macrolide antibiotic, was first used for the treatment of severe asthma in 1959 when it was shown to reduce the volume of sputum and the need for corticosteroids in ‘infectious’ asthma.2 This was confirmed in the late 1960s in adults and children with severe steroid resistant asthma when TAO was shown to significantly decrease the dose of oral corticosteroid needed for asthma control.3 Macrolide immunomodulatory therapy began in earnest in Japan starting in the early 1980s and dramatically improved survival in patients with diffuse panbronchiolitis (DPB).4

Outside asthma therapy, these properties have been clinically exploited in paediatrics only in the last few years. In 1992, EM was first successfully used to treat a native Japanese 16 year old with cystic fibrosis (CF) based on similarities between CF and DPB.5 Although for many years it was difficult to gain acceptance of these compelling data outside Asia, in recent years European and North American clinical trials in CF have documented significant improvement in lung function and quality of life (QOL) along with fewer exacerbations when using either CAM or AZM.6 There is increasing interest in the use of macrolides as adjunctive therapy for the treatment of other chronic inflammatory airway diseases.5, 7

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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 adverse events and greater activity against Haemophilus influenzae than EM. The dose of CAM is usually 15mg/kg/day divided every 12h for 10 days. The AZM dosage is 10mg/kg on the first day, then 5mg/kg once daily for 2–4 days. This provides prolonged tissue levels for the therapy of most infections.9 All of these agents display large volumes of distribution with excellent uptake into respiratory tissues, inflammatory cells and mucus relative to serum.10

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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 cytochrome P450 in the liver. EM given systemically in the first 2 weeks of life has been reported to increase the risk of hypertrophic pyloric stenosis.

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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

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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 composition from 2.44%±0.29 to 3.01%±0.20 and increased the sputum elastic (storage) modulus from 66±7 to 87±8dyne/cm2, without changing dynamic viscosity.14 CAM and EM may inhibit mucus secretion by down-regulating MUC5AC mucin mRNA expression as demonstrated in NCI-H292 cells and human nasal epithelial cells.15 AZM inhibits MUC5AC activated by 3O-C12-HSL in the NCI-H292 epithelial cell line. Extracellular signal-regulated kinase (ERK) 1/2 and MUC5AC protein were suppressed by AZM and MUC5AC protein was inhibited by a specific ERK inhibitor.16

EM can regulate water secretion by inhibiting Cl- and water efflux through the Ca-activated Cl channel and the CF transmembrane ion regulator (CFTR). However, there are no data clearly documenting whether macrolides have an effect on mucociliary transport, mucus viscoelasticity or airway ciliary beat frequency.17

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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 inhibiting the guanosine diphospho-d-mannose dehydrogenase (GMD) cycle19 or by preventing fimbriae-dependent twitching motility.20 Flagellin, a major component of the bacterial filament, enables motility in a wide range of bacterial species. Macrolides decrease flagellin expression and P. aeruginosa motility21 and piliated P. aeruginosa exposed to EM has decreased adherence to acid-injured mouse tracheal epithelia.22 Pseudomonas aeruginosa adherence to CF buccal epithelial cells was reported to decrease with low concentration AZM in vitro23 and EM reduces P. aeruginosa adherence to Type 4 basement membrane collagen in vitro.24 EM at sub-inhibitory concentrations suppresses P. aeruginosa lectins, cell surface haemagglutinating activity, extracellular protease and haemolytic activity and autoinducer formation.25 Macrolides suppress synthesis of the major stress protein, Gro-EL, in P. aeruginosa at concentrations below the MIC90. This may be associated with the inhibition of P. aeruginosa virulence and can induce bacterial death with longer incubation.26 At concentrations below the MIC90, CAM, EM and AZM kill Pseudomonas in a concentration-dependent manner, if there is an exposure time of 48h or more.27

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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 neutrophils stimulated by N-formyl-methionyl-leucyl-phenylalanine (fMLP).29 Ketolides can attenuate phospholipid-induced epithelial injury.30

EM can increase intracellular cAMP accelerating PMN apoptosis.31 RXM induced apoptosis of Dermatophagoides farinae-activated lymphocytes from subjects with D. farinae-sensitive asthma by induction of the Fas/Fas ligand system and reduced Bcl-2 expression.32

Macrolides inhibit the expression of adhesion molecules such as ICAM-1. EM reduces soluble intercellular adhesion molecule-1 (sICAM-1) secretion from cultured bronchial cells33 and down-regulates the expression of the β2-integrins (CD11b/CD18) by PMNs.34 RXM inhibits the expression of E-selectin and ICAM-1 in endothelial cells.35

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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 suppress cytokines including IL-1β and tumour necrosis factor-α (TNF-α) in monocytes,39 IL-1β, IL-6, TNF-α and granulocyte-monocyte colony-stimulating factor (GM-CSF) in mast cells40 and IL-8, epithelial cell derived neutrophil attractant-78 (ENA-78) and macrophage inhibitory protein-1 (MIP-1) in macrophages and leukocytes.41 RXM dose dependently inhibits both IL-4 and IL-5 secretion in T cells but has no effect on IL-2 or IFN-γ secretion.42 EM, RXM and josamycin (JM) decrease inducible nitric oxide synthase (iNOS) expression in IgG immune-complex stimulated alveolar macrophages.43 EM and CAM both suppress endothelin-1 mRNA and protein secretion from NHBE and this may attenuate the bronchoconstrictor response.44

Data suggest that macrolides decrease both activator protein-1(AP-1) binding sites and nuclear factor kappa B (NFκB) during nuclear transcription.45, 46 EM can suppress IL-1β-induced cyclooxygenase (COX-2) protein expression and inhibit IL-1β-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation associated with COX-2 expression in synovial cells.47

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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±0.5U×10−3/culture and IL-2 by splenocytes from 1.36±0.56 to 4.47±1.34U/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) release from endothelial cells51 and this may increase airway and vascular smooth muscle tone, neural signalling and host defence.

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CLINICAL USE OF MACROLIDES AS IMMUNOMODULATORY AGENTS 

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 600mg daily for 12 months, sputum production decreased from 70 to 10ml/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 months. Forced vital capacity (FVC) improved from 62.8% to 70.3% (P<0.03) and % forced expiratory volume (%FEV) also improved from 47.5% to 49.5% (P<0.03). In the USA, a very small single-blind prospective study was conducted in adults with CF using CAM 500mg bid for only 6 weeks.53 There was no significant difference in pulmonary function, sputum neutrophil count, IL-8, neutrophil elastase (NE) or myeloperoxidase (MPO). However, a larger study of 27 CF children (mean age 12 years) showed marked reduction of TNF-alpha, IL-8, IL-4, interferon-γ (IFN-γ) in sputum and plasma and increased the IFN- γ/IL-4 ratio and peripheral blood lymphocyte response to phytohaemagglutinin after being treated with CAM 250mg every other day for 12 months.54 These differences in pulmonary function and inflammatory markers could be due to different durations of therapy or to differences in study design.

In a 3 month prospective randomised, blinded and placebo-controlled study of AZM (250mg/day) in CF, a 1% increase in %FEV1 and %FVC predicted was maintained in the AZM group whereas in the placebo group there was a mean (± standard error (SEM)) decline of −3.62 (±1.78%) (P=0.047) in FEV1 and −5.73 (±1.66%) (P=0.001) in FVC.55 There were fewer total days of intravenous antibiotic treatment for acute respiratory exacerbations (P=0.009), fewer days of home intravenous antibiotics (P=0.037), fewer courses of intravenous antibiotics (P=0.016) and fewer days spent in hospital for antibiotic treatment of acute respiratory exacerbations (P=0.056) in patients on AZM. Median C reactive protein (CRP) in the AZM group decreased from 10 to 5.4mg/ml compared to the placebo group (P<0.001). Quality of life (QOL) in the AZM group improved over time (P=0.035).

A 15-month prospective blinded and placebo-controlled, crossover trial of AZM was then conducted in 41 children with CF aged 8 to 18 years.6 Subjects were given AZM 250mg/day (weight ≤40kg) or 500mg/day (weight >40kg) for 6 months. The mean (95% confidence interval (CI)) change in FEV1 from baseline was greater at all points in the AZM treatment group and the median relative difference was 5.4% (95% CI=0.8–10.5). This improvement with AZM for 6 months in FEV1 is similar to the 5.8% improvement seen with dornase alfa (Pulmozyme, Genentech, SD. San Francisco, CA).56 The median change in FEV1 for the 26 children not receiving concurrent treatment with dornase was 11.5% while that for the 15 children receiving dornase was −3.6%.

To confirm these results, a large placebo-controlled study was conducted at 23 CF centres in the United States.57 Subjects received AZM 250mg/day (weight <40kg, n=15) or 500mg/day (weight ≥40kg, n=72) 3 days a week for 168 days. Those taking AZM had a mean 0.097±0.26 L increase in FEV1 compared with 0.003 ± 0.23 L in the placebo group (95% CI=0.023–0.165; P=0.009), a 4.4% increase in %FEV1 compared with −1.8% in the placebo group, a 0.14 L increase in FVC compared with 0.02 L (P=0.01) and a %FVC of 3.7% compared with −1.3%. Subjects in the AZM group had fewer exacerbations (95% CI=0.44–0.95; P=0.03), gained an average of 0.7kg more weight (95% CI=0.1–1.4; P=0.02) and reported improvement in physical functioning on a QOL questionnaire (95% CI=0.1–5.3; P=0.05), compared with subjects receiving placebo. Adverse reactions attributed to AZM were nausea, diarrhoea, wheezing and hearing impairment (Table 1). However, side effects were generally mild and self-limiting.

Table 1. A summary of clinical trials in children using macrolides for asthma, cystic fibrosis or chronic sinusitis.
DiseaseAuthor and reference numberNo. of patientsAgeStudy designTherapy (duration)FindingsAdverse reactionsCinical effects
Steroid-dependent asthmaEitches et al. (1985) [75]1111 (7–13)Prospective studyTAO 14mg/kg/day, step down (12–28 months), methylprednisolone, theophyllineFEV1 increasing of 81%, FEV25-75 increasing of 93%, fewer emergency visits, fewer hospitalizations, missing fewer days of schoolTransient-increased cushingoid features, abdominal pain, liver enzyme level elevation+

Severe asthmaBall et al. (1990) [76]1513.5 (8–18)Randomized, parallel, double-blind placebo-controlledTAO 250mg once daily or every other day (2 weeks), glucocorticoidDecrease bronchial hyperresponsiveness to methacholineNo patient required rescue therapy+

Steroid-dependent asthmaFlotte et al. (1991) [66]98.3 (2.9–14.3)Prospective studyTAO 250mg once daily or every other day (4–34 months), methylprednisoloneDecreased steroid dosage, the number of steroid bursts (P<0.01), fewer hospitalizations (P<0.05)Increased the prevalence of cataracts (P=0.15), hypercholesterolemia (P<0.001)caution

Severe, steroid requiring asthmaKamada et al. (1993) [77]1812.5 (6–17)Randomized, parallel, double-blindTAO 250mg once daily or every other day (12 weeks), glucocorticoidReduction in glucocorticoid dose, No decrease bronchial hyperresponsiveness, No improvement pulmonary functionElevated liver enzyme level?

CFNakanishi et al. (1995) [5]116Case reportEM 600mg (>12 months)Decrease in sputum production, improvement in the finding of chest X rayNone+

CFJaffe et al. (1998) [52]712.1 (5.8–16.8)Open studyAZM daily (>3 months)11% improvement in FVC% and FEV1 (P<0.03)?+

CFOrdonez et al. (2001) [53]1023.6 (19–26)Single-blind prospective studyCAM 500mg BID (6 weeks)No changes in VC% and FEV1, no changes in BALF neutrophil cell count, IL-8, NE and MPO?−

CFWolter et al. (2002) [55]6027.9 (18–44)Prospective randomized double blind, placebo controlled studyAZM 250mg/day (3 months)Significant difference in change in FEV1 (P=0.047) and FVC (P=0.001), significantly improved QOL (dyspnoea scores: P=0.042), reduced CRP (P<0.001), reduced the number of respiratory exacerbations (P<0.001)AZM: 9 events, Placebo: 7 events. AZM: 2 discontinued treatment (“likely”: urticarial reaction, “possibly”: neutropenia), 1 “possibility” rash. No complication.+

CFEqui et al. (2002) [6]4113.8 (8.1–18.6)Randomized double-blind, placebo-controlled crossover trialbodyweight < or=40kg: AZM 250mg/day daily, bodyweight > 40kg: AZM 500mg/day (6 months)The median relative difference in FEV 1 between AZM and placebo: 5.4% (95% CI=0.8–10.5), fewer antimicrobial courses, no change in exercise tolerance or subjective well-being, sputum bacterial densities, and inflammatory markersNo noticeable adverse reactions. No abnormal clotting results. 12 of 190 patients failed hearing tests but all passed on retesting.+

CFSaiman et al. (2003) [57]18520.2 (SD: 7.9)Multicenter randomized, double-blind, placebo-controlled trialbodyweight< 40kg: AZM 250mg/day 3 days a week, bodyweight> or = 40kg: AZM 500mg/day 3 days a week (for 168 days)Significant improvement in percent predicted FEV1 (P=0.001) and FVC, fewer exacerbation (P=0.03)Nausea 17% more (95% CI=5–29%; P=0.01), diarrhoea 15% more (4–25%; P=0.009), wheezing 13% more (4–23%; P=0.007), No significant difference in laboratory abnormalities. Hearing impairment: 1(each AZM and placebo), tinnitus: 1(each AZM and placebo, discontinued treatment: 3 AZM (sore feet and bruising, sinusitis, ankle pain), 2 placebo+

Chronic sinusitis and/or chronic otitis mediaIino et al. (2003) [78]736.0 (1–14)Prospective controlledCAM 5–8mg/kg divided into twice-daily (8–15 weeks)63% children with chronic rhinosinusitis and 35% with OME, free of the diseases. Clinical efficacy depend on anti-inflammatory effects, independent of antimicrobial effects?+

TAO, troleandomycin; FEV1, forced expiratory volume in 1 second; CF, cystic fibrosis; EM, erythromycin; AZM, azithromycin; CAM, clarithromycin; FVC, forced vital capacity; QOL, quality of life; CRP, C reactive protein;CI, confidence interval; OME, otitis media with effusion.

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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 (150mg bid for 3 months), there was increased pulmonary function and decreased IL-8, NE and leukotriene (LTB4) in BALF.61 Data also suggest that CAM can reduce the size of nasal polyps and IL-8 levels in nasal lavage in patients with inflammatory sinusitis and polyposis.62

Diffuse panbronchiolitis (DPB) is a severe sinobronchial syndrome most commonly reported in East Asia. It has many similarities to CF airway disease including chronic progressive sinusitis and bronchiectasis associated with mucoid strains of P. aeruginosa. It usually begins in the third or fourth decade of life, but can begin in adolescence according to the Diffuse Lung Disease Committee of the Ministry of Health and Welfare in Japan (DLDC). Macrolide therapy has proven dramatically beneficial, even in patients with DPB infected with P. aeruginosa resistant to macrolide antibiotics.63 Low-dose, long-term EM therapy (400–600mg/day) was shown in the early 1980s to improve the survival of patients with DPB from 26% to 94%.4, 64 In a prospective open label trial of oral CAM (200mg once a day) for 4 years, subjects with DPB had a significant improvement of FEV1 from 1.74±0.12 L to 2.31±0.22 L (P<0.01) and FVC from 2.67 to 3.16L within 6 months. All patients continued to improve or remained stable with continued therapy.65 There were no significant adverse events attributed to the macrolide reported over 4 years.

The DLDC recommends the following:64

1)EM at 400 or 600mg/day should be started once the diagnosis is established and therapy should continue for at least 6 months

2)After 6 months, CAM 200 or 400mg/day or RXM 150 or 300mg/day can be used for EM non-responders or if there are intolerable side effects (principally gastrointestinal disturbance).

3)Therapy should continue for 2 years as long as the patient is improving and can be stopped after 2 years if the patient is clinically stable.

4)Therapy should be restarted if symptoms reappear after stopping treatment.

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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 500mg 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. In a randomised double-blind placebo-controlled study, CAM 750mg/day for 8 weeks increased the provocative dose of methacholine that would cause a 20% fall in FEV in 1 s (PD20) from 0.4mg to 2mg and improved %FEV1 predicted from 85±13% to 88±12%.69

Some asthma exacerbations are associated with infection by organisms such as Chlamydia pneumoniae or Mycoplasma pneumoniae and persistent infections by these organisms may contribute to the severity of asthma.70 Subjects with severe asthma who had positive polymerase chain reactions (PCRs) for M. pneumoniae or C. pneumoniae in airway secretions significantly improved their FEV1 from 2.50±0.16 to 2.69±0. 19 L after therapy with CAM 500mg bid for 6 weeks.71

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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 disease. It can be classified as inflammatory or acellular based on the histological appearance of the casts. The presence of large, obstructive plugs filling the airways of lobes or entire lungs can result in a variety of clinical signs and symptoms and may ultimately lead to respiratory failure and death.72 Conventional treatment of plastic bronchitis has focused on the clearance of obstructing material from the airways combined with therapy for any underlying cardiopulmonary disease. Unfortunately, this approach has not proven very effective and patient mortality remains high. Shultz and colleagues reported a patient with cast bronchitis who was treated with long-term, low-dose oral AZM. This therapy resulted in clinical, spirometric and radiographical improvement.73

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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 has been reported in North America in proportion to the amount of antibiotics prescribed and mefB resistance is extremely common in Asia. Tolerance to the non-antimicrobial immunomodulatory effects has not been reported. Research is progressing to develop macrolides that lack antimicrobial properties but retain immunomodulatory properties with the aim of decreasing the opportunity for antimicrobial resistance to develop.

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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 or clarithromycin.

•Both clarithromycin and azithromycin accumulate in tissues producing clinical effects of prolonged duration.

•With long term use, bacteria can develop low grade resistance to macrolides by activating efflux pumps (mef) or high grade resistance by changing the ribosomal binding site (erm).

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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.

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Acknowledgments 

The authors thank Lauren Clarkson and Samir A. Shah for editorial assistance.

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PII: S1526-0542(05)00050-3

doi:10.1016/j.prrv.2005.06.005

Paediatric Respiratory Reviews
Volume 6, Issue 3 , Pages 227-235, September 2005

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