CLArithromycin Versus AZIthromycin in the Treatment of Mycobacterium Avium Complex (MAC) Lung Infections

1. Scientific rationale and general description:

Nontuberculous mycobacteria (NTM) represent all mycobacteria not belonging to the Mycobacterium tuberculosis complex. This group of mycobacteria was discovered recently and has demonstrated pulmonary pathogenicity. The presence of a NTM in a respiratory specimen is therefore not sufficient to confirm the diagnosis of a lung infection. The ATS/IDSA 2007 guidelines require clinical, radiological and microbiological criteria to distinguish infection from colonisation.

The main NTM isolated and responsible of NTM pulmonary infections in France is Mycobacterium avium complex (MAC). MAC organisms are common in many environmental sites, including water, soil and in animals. Up to now, the main hypothesis for transmission is inhalation of MAC via aerosol during the shower. Three classical clinical and radiological patterns are described for MAC: the fibrocavitary lung disease, the nodular bronchiectatic disease and the hypersensitivity disease. This last pattern classically doesn't need any antibiotics. So, this study will focus only on the two first patterns: fibrocavitary form and nodular-bronchiectatic form.

The limitations for effective therapy were the absence of antimicrobial agents with low toxicity and good in vivo activity against the organism. The major therapeutic advance is the introduction of the newer macrolides, clarithromycin and azithromycin, which have substantial efficacy in vitro and clinical activity against MAC. Structurally, azithromycin is an azalide. However, because of the close similarity of azalides to macrolides, the term "macrolide" is often used to refer to azithromycin and clarithromycin. As macrolides are the cornerstone of MAC treatment, their use in monotherapy is responsible of selection of macrolides MAC resistant strains that are associated with microbiological and clinical relapse. This is why all international guidelines and all experts recommended the use of macrolides with at least two companion drugs, classically rifampicin and ethambutol.

Treatment of MAC lung disease is long and not well tolerated. Despite treatment, microbiological failure or early relapse occurs in 20-30% of patients. One of the main failure explanations in NTM disease is the spontaneous treatment stop by the patient, due to adverse effects. Even if clarithromycin is often used in first line in France and is the only one macrolide with indication in its Summary of Product Characteristics, its tolerance is often poor. Adult patients generally cannot tolerate clarithromycin at more than 1,000 mg/day. The most common toxicities seen with clarithomycin are gastro-intestinal (metallic taste, nausea, and vomiting) and it interacts with numerous drugs via P450 cytochrome. Moreover, clarithromycin enhances rifabutin toxicity, especially uveitis. Azithromycin toxicity is dose and serum-level related. Most adult patients with MAC lung disease do not tolerate azithromycin doses of greater than 300 mg/day because of frequent adverse events, including gastrointestinal symptoms (primarily diarrhea).