In Vitro Synergy between Clofazimine and Amikacin in Treatment of Nontuberculous Mycobacterial Disease

Abstract

Disease caused by nontuberculous mycobacteria (NTM) is increasing in frequency. The outcome of treatment for NTM lung disease is poor, particularly lung disease caused by Mycobacterium simiae and M. abscessus. Exploring synergy between active available drugs is a sensible way forward given the lack of new active drugs. We tested for synergy between amikacin and clofazimine, using standardized methods, in 564 consecutive clinical isolates identified as 21 species of rapidly growing mycobacteria, 16 clinical M. avium complex isolates, and 10 M. simiae isolates. Clofazimine and amikacin are each active in vitro against NTM; 97% (n ‫؍‬ 548) of the rapid growers revealed MICs of clofazimine of <1 g/ml, and 93% (n ‫؍‬ 524) proved susceptible to amikacin. The combination showed significant synergistic activity in 56 of 68 (82%) eligible M. abscessus isolates, 4 of 5 M. chelonae isolates, and 1 M. fortuitum and 1 M. cosmeticum isolate, with 4-to 8-fold decreases in MICs to both drugs. Significant synergy could also be demonstrated against all M. avium complex and M. simiae isolates, with fractional inhibitory concentrations of <0.5. Clofazimine and amikacin show significant synergistic activity against both rapidly and slowly growing nontuberculous mycobacteria. The safety and tolerability of adding clofazimine to amikacin-containing regimens should be tested in clinical trials, and the results of susceptibility tests for these two compounds and their combination merit clinical validation. Synergy between clofazimine and other antibiotics with intracellular targets should be explored. Disease caused by nontuberculous mycobacteria (NTM) is increasing in frequency in many parts of the world, especially those where the incidence of tuberculosis is in decline (23). NTM are divided into slow growers (e.g., Mycobacterium avium complex, M. kansasii, and M. simiae) and rapid growers (e.g., M. abscessus, M. chelonae, and M. fortuitum). Within these groups, treatment regimens and treatment outcomes differ by species (8). In general, treatment outcomes are poor, but they are particularly so in lung disease caused by M. simiae and M. abscessus (8,9,10,19). Unfortunately, there are few new active drugs available, so exploration of synergistic activity may provide means to develop better treatment regimens utilizing the most active combinations of existing drugs.Clofazimine, a drug designed for tuberculosis treatment though mainly used in the treatment of leprosy (14), is among the active existing drugs that could be of use in itself and as an adjunctive drug. Clofazimine has been used as a replacement for rifampin, with similar outcomes, in lung disease caused by M. avium complex (MAC) (6). Recently, in vitro evidence for synergy between clofazimine and amikacin was recorded in rapidly growing NTM species, including M. abscessus, M. chelonae, and M. fortuitum (17). The potential of clofazimine combined with amikacin warrants investigation in both slow and rapid growers, as amikacin is an important cornerstone of therapy for disease ...

Clofazimine Prevents the Regrowth of Mycobacterium abscessus and Mycobacterium avium Type Strains Exposed to Amikacin and Clarithromycin

“…Clofazimine is the prototype riminophenazine antibiotic with in vitro activity against most mycobacteria (1,4). Its main clinical use so far is in the multidrug treatment of leprosy and multidrugresistant tuberculosis (18).…”

“…Previous studies showed in vitro synergy between clofazimine and amikacin against both rapidly and slowly growing NTM (1,6). The combination clarithromycin-clofazimine also showed synergy against MAC strains in checkerboard evaluation (7).…”

“…Treatment outcomes are generally poor, and current treatment recommendations have a very limited evidence base, since very few clinical trials have been performed (1,2).…”

Disseminated Infection by Mycobacterium sherrisii and Histoplasma capsulatum in an African HIV-Infected Patient

“…We suggest two possible explanations: first, the initiation of HAART treatment in the HIV cases improves the immunological status of the patient; and second, the combination of antibiotics could act synergistically improving antimycobacterial drug activity. Indeed, two studies showed in vitro synergy in non-tuberculous mycobacteria, which included M. simiae and related species 11,12 ; an alternative to the classic AST could be the synergy study of the drugs used.…”

Response to Switch from Intermittent Therapy to Daily Therapy for Refractory Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease

“…Further studies will be needed to differentiate treatment failure from reinfection and to identify better therapeutic regimens with the addition of potentially effective drugs, such as intravenous or inhaled amikacin, inhaled liposomal amikacin, fluoroquinolones, and clofazimine, in these patients with NB MAC-LD (26)(27)(28)(29).…”