Prevalence of nontuberculous mycobacteria and high efficacy of D-cycloserine and its synergistic effect with clarithromycin against <em>Mycobacterium fortuitum </em>and <em>Mycobacterium abscessus</em>

Abstract

BackgroundThe prevalence of pulmonary disease caused by nontuberculous mycobacteria (NTM) is reportedly on the rise in the world. Some of the species are resistant to various antibiotics; hence, limited treatment options are available. The aims of this study were to investigate the prevalence of NTM and to determine the effect of d-cycloserine against Mycobacterium fortuitum and Mycobacterium abscessus isolated from clinical specimens to find out the synergistic effect of d-cycloserine and clarithromycin.MethodsA total of 95 nonduplicate pulmonary isolates of NTM were collected from three major Regional Tuberculosis (TB) Centers. NTM isolates were identified by conventional tests and PCR sequence analysis of the rpoB gene. PCR sequencing of erm-41 was performed for detecting the inducible resistance to macrolides. In vitro susceptibilities and activities of d-cycloserine-clarithromycin combinations were accessed using the broth microdilution method.ResultsAmong 714-positive acid-fast bacilli from TB-suspected cases, 95 isolates were identified as NTM (13.3%). The prevalence of identified isolates was as follows: M. fortuitum 46 (48.4%), Mycobacterium simiae 16 (16.8%), Mycobacterium kansasii 15 (15.7%), M. abscessus 7 (7.3%), Mycobacterium thermoresistibile 4 (4.2%), Mycobacterium elephantis 3 (3.2%), Mycobacterium porcinum 2 (2.1%), and Mycobacterium chimaera 2 (2.1%). In addition, rpoB sequence analysis could identify all NTM isolates. The effect of d-cycloserine was better than that of clarithromycin. The synergistic effect of d-cycloserine with clarithromycin was observed for six (100%) and five (71.5%) strains of M. fortuitum and M. abscessus, respectively.ConclusionIn the present study, we demonstrated a wide range of NTM in processed samples from different provinces of Iran. Our observations indicated that d-cycloserine was very active against M. abscessus and M. fortuitum; hence, d-cycloserine, either alone or in combination with clarithromycin, may be promising for the treatment of M. abscessus- and M. fortuitum-associated diseases.

Loperamide exerts a direct bactericidal effect against M. tuberculosis , M. bovis , M. terrae and M. smegmatis

“…We found that loperamide was able to inhibit the growth of tuberculous mycobacteria such as M. tuberculosis and M. bovis BCG and both slow-growing (M. terrae) and fast-growing (M. smegmatis) non-tuberculous mycobacteria that have been reported to cause lung disease (Driks et al 2011;Henkle and Winthrop 2015). Due to these inhibitory properties, loperamide may be considered in NTB treatment, since these Mycobacteria are intrinsically resistant to most firstline antibiotics used to combat tuberculosis (Khosravi et al 2018). Although the MICs may appear high, we found that loperamide was able to significantly inhibit mycobacterial growth of all strains at very low concentrations (12Á5 and 18Á7 lg ml À1 ), which suggests a therapeutic value for loperamide that may be worth investigating, either alone or in combination with conventional chemotherapy.…”

Severe Pulmonary Mycobacterium abscessus Cases Due to Co-Infection with Other Microorganisms Well Treated by Clarithromycin and Sitafloxacin in Japan

“…MICs were measured on day 3 or 4 and compared with control wells without antibiotics, showing sufficient bacterial growth. 8 MIC was defined as the lowest drug concentration at which bacterial growth was not visualized. The isolated organisms were resistant to most of the other antibiotics, including levofloxacin and moxifloxacin.…”

Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

“…A number of drugs targeting various aspects of peptidoglycan biosynthesis have shown activity against M. abscessus in vitro, if not in vivo. These include d ‐cycloserine which targets the alanine racemase (Alr) and the d ‐Ala‐ d ‐Ala ligase (DdlA) 47 ; the capuramycin analogue, SQ641, which targets the phospho‐ N ‐acetylmuramyl pentapeptide translocase (MraY) 48 ; glycopeptides vancomycin and teicoplanin which bind to the d ‐Ala‐ d ‐Ala terminal amino acids of the peptide chains and, in doing so, prevent cross‐linking and other processes in the final assembly of peptidoglycan 44,49 ; and β‐lactams which target d , d ‐transpeptidases (also known as penicillin‐binding proteins) and the nonclassical l , d ‐transpeptidases 50 . The lack of susceptibility of l , d ‐transpeptidases to penicillins 50 combined with the presence of β‐lactamases 51 accounts for the natural resistance of M. abscessus to most β‐lactams.…”

“…d ‐Cycloserine, an old antituberculosis drug, has been shown to be active against M. abscessus clinical isolates with MICs in the range of 8.0–32.0 μg/ml, and to potentiate the activity of clarithromycin used in combination 47 …”