ANTHELMINTIC AVERMECTINS FOR THE TREATMENT OF NON-TUBERCULOUS MYCOBACTERIA INFECTIONS IN CYSTIC FIBROSIS
Introduction. Pulmonary disease caused by non-tuberculous mycobacteria (NTM) has emerged as a major threat to the health of individuals with cystic fibrosis (CF). The NTM most commonly identified in individuals with CF belong to the Mycobacterium abscessus (MABSC) and Mycobacterium avium (MAC) complexes. CF patients infected with NTM require prolonged multidrug treatment courses but, nevertheless, the probabilities of being cured are low. New therapeutic options are needed to improve therapy outcomes.
Avermectins are a family of macrocyclic lactone compounds usually used as anthelmintic drugs for clinical and veterinary uses. Although inactive against Gram-positive and Gram-negative bacteria, they have demonstrated in vitro activity against mycobacterial species, including Mycobacterium tuberculosis (PMID: 23165468), Mycobacterium ulcerans and Mycobacterium marinum (PMID: 26270480).
Objectives. The aim of this study is to evaluate the in vitro activity of the avermectins against MABSC and MAC.
Methods. Four bacterial strains were analyzed: M. avium ATCC 25291, M. abscessus sb. abscessus ATCC 19977, M. abscessus sb. bolletii CCUG 50184 and M. abscessus sb. massiliense CCUG 48898. Avermectins tested, both veterinary and clinically used, included: abamectin, doramectin, emamectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, and selamectin. Antimicrobial susceptibility testing was carried out by broth microdilution MIC and time-kill assays in 7H9-based medium (PMDI: 27678056).
Results. Ivermectin, doramectin, selamectin, emamectin and milbemycin oxime were active against the NTM tested. Milbemycin oxime had relatively low MIC values (MIC = 8 µg/mL) against all the strains, while ivermectin and doramectin showed potent activity only against M. abscessus sb. abscessus (MIC= 1-2 µg/mL) and selamectin was active only against M. avium (MIC= 2 µg/mL). There were no differences in the MIC values of milbemycin oxime when measured at three and fourteen days of incubation; this is an improvement over the first-line drug clarithromycin that also contains a macrocyclic ring, for which induction of resistance through the erm gene compromised its clinical effectiveness.
To answer the question of whether avermectins were bactericidal or bacteriostatic, kill kinetic experiments were performed for the most active compounds, ivermectin and milbemycin oxime. Ivermectin showed inhibitory activity against M. abscessus sb. abscessus, but after 3 days of incubation the strain did resume growth, while no inhibition was observed against any of the other strains tested. Milbemycin oxime displayed inhibitory activities against all strains tested and bactericidal activity against M. abscessus sb. massiliense.
Conclusions. Milbemycin oxime was the most active avermectin against MABSC and MAC strains, although its bactericidal activity was only confirmed against M. abscessus sb. massiliense; this could be related to the fact that this strain carries deletions in the erm gene.
The avermectins are clinically approved drugs. Many of them are for veterinary used (i.e. milbemycin oxime), however, extensive packages of pharmacological and toxicity data are readily available. Although more studies are needed to assess their clinical potential, they could form the basis of new therapeutic approaches (alone or in combination) against NTM infections.