CFDB - Cystic Fibrosis DataBase

Anti-inflammatory therapy

Azithromycin

Background

Prevention of lung deterioration is one of the most important goals in Cystic Fibrosis therapy, because 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. 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). Azithromycin efficacy  against P.a.  has been studied recently in a rat  lung infection model  ( Kumar M, 2021

International Giudelines (Mogayzel P. 2013) had affirmed that the use of chronic Az, above all in patients infected by P.a., is recommended., even if Az administration should be avoided in the presence of severe hepatic or renal involvement. After 6 months, of treatment the drug should be discontinued if no observable effects  are 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 non-tuberculous mycobacteria (NTM).  

No sure adverse events related to Az use are reported in CF patients. 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, but it has been affirmed (Albert RK, 2014), that the large majority of subjects experiencing cardiac arrhythmias from macrolides, have other co-existing risk factors. In 2019 (Avedissian SN ,2019), a retrospective study conducted over a 3-year period in an adult CF center, did not show any  association between chronic Az therapy and longer QTc intervals or significant QTc prolongation. In children too, Az long-term use ( Magaret A, 2021) has shown no association with QTc prolungation. Recently (Song Y, 2021) it has been reported an unusual side effect of first degree heart block after 8 months of Az in combination with tezacaftor/ivacaftor CFTr modulator.  

The hypothesized Az role in increasing the risk for  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 more recent study (Cogen JD, 2018), in which data about 26.914 patients from the Patient Registry U.S.A, were collected, showed that chronic  Az  users had a lower risk of acquiring several CF-related respiratory pathogens including NTM. Moreover, In 2021 ( Richter W, 2021)  low rates of macrolide-resistant Mycobacterium avium complex was shown, despite chronic Az therapy.

Concerns have emerged about the concomitant use of Az and Tobramycin in pulmonary exacerbations (Cogen JD, 2021) and Az therapy during pregnancy (Taylor-Coursar J, 2021)

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. 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.

A meta-analysis ( Reynaud Q, 2020)  about risk factors for nontuberculous mycobacterial isolation has not found Az therapy between them.

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.

In 2020 one RCT (Magaret AS, 2020) about 221 CF children showed that long-term chronic azithromycin use, with a median of 18 months follow-up,  was not associated with increased QT prolongation.

In 2021 (Akkerman-Nijland AM, 2021) an observational controlled study observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years.

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;