MACROLIDES

1997 Everard ML, Sly P, Brenan S, Ryan G. Macrolides antibiotics in diffuse panbronchiolitis and in cystic fibrosis. Eur Respir J 1997; 10:2926. [PubMed]
Mark Everard (figure 41) confirmed with me that this was the first combined report from Sheffield, UK and Perth, Western Australia showing the anti-inflammatory effect of macrolides in people with cystic fibrosis. Four of six patients with CF had significant reduction in IL-8 sputum levels after one month treatment with low dose (200 mg tds) oral erythromycin. He believes the first report of the use of macrolides in CF was in a Japanese publication by Nakanishi et al in 1995 – "A 16-year-old boy was admitted to our hospital because of coughing, sputum, and exertional dyspnoea. Seven months after birth cystic fibrosis had been diagnosed. The chest roentgenogram on admission showed diffuse reticulonodular shadows and overinflation. Pulmonary function tests revealed obstructive and restrictive impairment. Erythromycin and Lomefloxacin were administered by mouth, and aminoglycosides were administered by inhalation. His symptoms were alleviated, and he is now an outpatient. In Japan, cystic fibrosis is rare, and this patient is extremely rare because he has grown up to be a 16-year-old. In this case, low-dose and long-term erythromycin administration was very effective". (Nakanishi N, Ueda N, Kitade M, Moritaka T. A case of cystic fibrosis in a Japanese student. Jpn J Thoracic Dis 1995; 33:771-774). [PubMed]

The beneficial effect of 600 mg/day of erythromycin for 1 to 12 months in chronic panbronchiolitis in Japanese patients had been reported previously (Nagai H et al. Respiration 1991; 58:145-149). [PubMed] The effect appeared to be independent of the presence of chronic Pseudomonas infection and an anti-inflammatory action was suggested (Fujii T et al. Thorax 1995; 50:1246-52; Hoiby N. Thorax 1994; 49:531-532; Kudoh S et al. Jpn J Thorac Dis 1987; 25:632-42; Kudoh S. et al. Am J Respir Crit Care Med 1998; 157:1829-32 below; Kudoh et al, 1998 below).

These were important developments eventually leading to a number of large clinical trials and the widespread use of azithromycin in people with CF – undoubtedly one of the major clinical treatment advances of the Nineties and new Millennium (Equi et al, 2002 below; Saiman et al, 2003 both below). By 2005 nearly 54% of all the patients on the CF Foundation Registry were taking azithromycin.

1998 Kudoh S. Azuma A. Yamamoto M. Izumi T. Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med 1998; 157:1829-32. [PubMed]
Diffuse panbronchiolitis (DPB) is a chronic inflammatory disease of the airways with a high mortality despite treatment with a combination of antibiotics and the use of supportive therapy. Low-dose erythromycin therapy (EM) (400 to 600 mg/d) improved the survival and most patients in Japan have been treated with this regimen since 1984. The authors compared the survival rates of 498 patients with DPB after dividing them into three groups (Group a: 1970-1979, Group b: 1980-1984, Group c: 1985-1990). The survival rate of Group c was significantly higher than that of Groups a (p < 0.0001) and b (p < 0. 0001). In Group c (1985-1990), eight of 87 patients died; five (21%) died in the EM non-treated subgroup (n = 24), and three (5%) died in the EM-treated subgroup (n = 63). So treatment with erythromycin was associated with a significant improvement in the survival of patients with DPB which was more significant in the older than in the younger patients.

These findings were the basis for the gradual evaluation of macrolide therapy in people with cystic fibrosis. The first report of the favourable effect of erythromycin in DPD was Kudoh S, et al. Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Jpn J Thorac Dis 1987; 25:632-642. Mark Everard et al, (1997 above) was the first in the UK to report an effect on sputum inflammatory markers in cystic fibrosis.

1998 Jaffe A, Francis J, Rosenthal M, Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998; 351:420. [PubMed]
The second very convincing observational study on macrolides and CF from the UK (first report by Everard et al, 1997 above) showing impressive improvement in the respiratory function of severely affected children given regular azithromycin in addition to their usual treatment. These impressive observations were followed by a controlled trial from the Brompton Hospital, London which confirmed the beneficial effect (Equi et al, 2002 below) and also by a major trial from the US CF Foundation (Saiman et al, 2003 below).

2002 Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 2002; 360:978-84. [PubMed]
A major UK trial of macrolides from the Brompton Hospital, London following the report of Jaffe et al, 1998 (above). 41 children with CF received azithromycin or placebo for 6 months in addition to their usual treatments. The median relative difference in FEV1 between azithromycin and placebo patients was 5.4%. However, this was made up as follows - FEV1 of 13 (31.7%) patients improved by more than 13% but five (12.2%) deteriorated by more than 13% (p=0.059). Seventeen (41.5%) of the azithromycin treated patients required fewer oral antibiotic courses but five had extra courses (p=0.005). Sputum bacterial densities, inflammatory markers, exercise tolerance, and subjective well-being did not change. There were no noticeable side-effects.

This was an important trial as it gave further support to one of the major new treatments of the Millennium which would become widely used not only in patients chronically infected with Pseudomonas but eventually also in younger uninfected patients. The clear importance of considering the effect of treatment on individual patients is apparent as the FEV1 of five children deteriorated by more than 13%.   It is interesting, and perhaps not without relevance in regard to the effects of macrolides, that Harry Shwachman used erythromycin on more severely affected patients and at times saw significant benefit; also Margaret Mearns in London used erythromycin in the young patients perhaps both these experienced clinicians appreciated that there was some additional effect from the macrolides? By 2006 no less than 57.3% of patients with CF in the USA were taking regular azithromycin.

Fig. 28: Professor Andy Bush

Prof. Andy Bush (figure 28) is paediatrician at the Royal Brompton Hospital, London and has been a leading researcher and clinician involved in CF from the early Nineties. This is one of the many important studies to come from the paediatric department at the Brompton where one of the early observations on the favourable effect of macrolides was published and undoubtedly stimulated further investigations into their possible role in cystic fibrosis treatment (Jaffe et al, 1998 above).

2003 Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY Accurso FJ Campbell PW. Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290:1749-56. [PubMed]
This is the major CF Foundation multicentre study on azithromycin. The active group (n = 87) received 250 mg (if weight <40 kg) or 500 mg (if weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; the placebo group (n = 98) received identically packaged tablets The azithromycin group had a significant mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group. Participants in the azithromycin group had less risk of experiencing an exacerbation and at the end of the study weighed an average 0.7 kg more than participants receiving placebo.

So here was further evidence that azithromycin treatment was associated with improvement in clinically relevant end points and the authors advised the drug should be considered for patients with CF who are 6 years or older and chronically infected. Following this trial the product was licensed and by 2005 53.6% of patients on the US CF Foundation Patient Registry were taking azithromycin.

2005 Hansen CR, Pressler T, Koch C, Hoiby N. Long-term azithromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study. J Cyst Fibros 2005; 4:35-40. [PubMed]
In 2001 long-term, low-dose azithromycin (AZ) treatment was introduced as an integral part of the routine treatment at the Copenhagen CF centre and 45 patients completed 1-year of treatment. The authors concluded that long-term, low-dose AZ treatment in adult CF patients with chronic P. aeruginosa infection was safe and reduced the rate of decline in lung function, increased weight, and reduced the percentage of mucoid strains of P. aeruginosa in sputum samples.
This was a useful observational study from a centre where the previous standard of treatment was known to be high – even so, there was further impressive improvement with the addition of azithromycin to their usual treatment regimen (also Everard et al, 1997; Jaffe et al, 1998; Equi et al, 2002; Saiman et al, 2003 all above).

Fig. 39: Dr Tacjana Pressler

Dr Tacjana Pressler (figure 39) succeeded the late Dr Christian Koch as Medical Director of the Copenhagen CF Centre (see www.Biomedexperts.com).

2006 Phaff SJ, Tiddens HA, Verbrugh HA, Ott A. Macrolide resistance of Staphylococcus aureus and Haemophilus species associated with long-term azithromycin use in cystic fibrosis. J Antimicrob Chemother 2006; 57:741-746. [PubMed]
The purpose of this study was to determine the association between long-term use of azithromycin, now taken by many patients with CF, and change over time in macrolide susceptibility of Staphylococcus aureus and Haemophilus spp. The authors found that erythromycin resistance in S. aureus increased from 6.9 to 53.8% and clarithromycin resistance in Haemophilus spp. from 3.7 to 37.5%. Resistance but also isolation rates were strongly related to azithromycin use.
So over a 4 year period, azithromycin maintenance therapy in the CF population was associated with an increase in macrolide resistance in S. aureus and Haemophilus spp. which was not unexpected.

There is an extensive literature on the use of macrolides in cystic fibrosis since 2006 including a Cochrane Review. Most seems to be favourable and support their use.

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