CFDB - Cystic Fibrosis DataBase

Anti-inflammatory therapy

Azithromycin

Background

Prevention of lung deterioration is one of the most important goals in Cystic Fibrosis therapy. Persistent pulmonary infection and the associated hyperactive inflammatory response cause  lung damage. Pseudomonas aeruginosa (P.a.), above all its mucoid phenotype, is  considered the most important pathogen in chronic airway infection.

Macrolides are an orally available class of antibiotics with a broad spectrum of action, mainly against gram-positive bacteria. In the last years it has been postulated, and also more recently confirmed (Shteinberg M, 2016),  that long-term use of macrolides at low dose can act indirectly against P.a. and as anti-inflammatory  agents. Moreover,  it has showed that macrolides decreased the minimal inhibitory concentration of anti-pseudomonal agents on biofilm-grown P.a. (Lutz L, 2012).

Azithromycin (Az) is the most studied macrolide, showing the most significant activity against P.a. virulence factors, an anti-inflammatory activity (Olveira C, 2017) and  a possible role in the management and prevention of RV-induced CF pulmonary exacerbations (Schögler A, 2015).  

International Giudelines (Mogayzel P. 2013) had affirmed that the use of chronic Az, above all in patients infected by P.a., is recommended. Az administration should avoided in the presence of severe hepatic or renal involvement and  minimal duration of the  treatment is 6 months, after which the drug should be discontinued if no observable effect is noted on clinical parameters, exacerbation rate and/or FEV1 values. More recently, (Abely M,2015) a National Consensus  in France validated  Az use as a long-term anti-inflammatory agent in children aged over 6 years, presenting with the classical form of CF, irrespective of the bacteriological status (except for NTM).  

No sure adverse events related to Az use are reported in CF patients. Indeed,  in patients affected by other diseases, it has been hypothesized (Ray WA, 2012) that Az may increase the risk of cardiovascular death, above all by severe arrhythmias. Even if it has been affirmed (Albert RK, 2014), that the large majority of subjects experiencing cardiac arrhythmias from macrolides, have other co-existing risk factors, more recently it has been suggested again (Lenehan P,2016) that  the QTc interval of CF patients, above all adolescent males,  should be monitored throughout the course of chronic Az therapy.

Moreover it has been hypothesized (Nick JA, 2014), and more recently suggested again (Nichols DP, 2017), that oral Az may antagonize the therapeutic benefits of inhaled tobramycin in CF subjects with P. a. airway infection. Finally, the hypothesized Az role in increasing the risk to non-tuberculous mycobacteria (NTM) infection (Renna M, 2012), has not been confirmed (Binder AM, 2013). On the contrary,  a study (Coolen N, 2015)  has suggested  that Az   may be  a primary prophylaxis for NTM infection in CF adults and  a recent other  study (Cogen JD, 2018), in which data about 26.914 patients collected in the Patient Registry U.S.A. have been investigated, found, in a predominantly pediatric cohort, that chronic  Az  users had a lower risk of acquiring several cystic fibrosis-related respiratory pathogens including NTM.

Issues

Azithromycin efficacy in preventing pulmonary deterioration, evaluated as lung function evolution, lung exacerbation frequency, quality of life and survival.                                                         

Short-term and long-term azithomycin therapy-associated adverse effects (gastrointestinal symptoms, liver problems, hearing impairment, acquisition by significant CF lung pathogens, change in antibiotic susceptibility pattern, cardiovascular problems).

Optimal therapy administration protocol.

What is known

One CDSR, updated November 2012 (Southern KW, 2012), included 10  RCT with 959 enrolled CF patients older than 6 years. In  8 studies, azithomycin(Az) was compared with placebo. Only adults were enrolled in one study and only children were enrolled in four, and  in one study only P.a.-positive patients were enrolled, whereas in another study only P.a.-negative patients were enrolled. 

In 2 studies, two different doses of Az were compared: one study compared high-dose and low-dose regimens and one study compared a once-weekly with a daily dose regimen. CDSR results suggest that Az, administered at the dosage of 500 mg (250 mg if weight is <40 Kg) three times a week, improves lung function and reduces pulmonary exacerbations, mainly in patients with chronic P.a. lung infection and during the first six months of treatment. With this dose regimen adverse events are uncommon, even if Staphylococcus aureus (S.a.) macrolide resistence increases.

One DARE review, updated in 2009, substantially reports the same results, even if nausea and diarrhoea were found more frequently associated with Az therapy.  

In a study published in 2012 it has been confirmed that Az is useful in patients uninfected with P.a., can reduce exacerbations and improve weight gain over 6-12 months among children and adolescentand.

A .RCT demonstrated that oral Az significantly reduced neutrophil counts and serum inflammatory markers within 28 days from the start of treatment.

In  2018 (Mayer-Hamblett N, 2018)  a multicenter, placebo-controlled, trial in children with CF with early Pa.isolation,  Az  resulted as associated with a significant reduction in risk of  BPN exacerbation and improvement in weight but  not with impact on microbiologic outcomes.

In 2019 (Nichols DP, 2019) a retrospective cohort study using the U.S. CF Foundation Patient Registry, showed that, across 3 years, FEV1 %/ year decline was nearly 40% less in those with P.aeruginosa  using azithromycin compared to matched and that this rate of decline did not differ based on azithromycin use in those without PA.

 

Unresolved questions

  • Efficacy and safety of azithromycin therapy over a more prolonged period of time, mainly in children, above all in pre-symptomatic ones.

No RCT are ongoing about this issue

 

Keywords: Anti-Inflammatory Agents; Macrolides;