Comparison of drug-susceptibility patterns and gene sequences associated with clarithromycin and azithromycin resistance in Mycobacterium abscessus complex isolates and evaluation of the accumulation of intrinsic macrolide resistance
Introduction.Mycobacterium abscessus complex (MABC) is an infectious agent associated with macrolide resistance and treatment failure.
Hypothesis/Gap Statement. Despite drug-susceptibility testing for MABC isolates including clarithromycin (CAM), long-term treatment with azithromycin (AZM) for MABC disease is recommended.
Aim. We compared phenotypic and genotypic resistance to AZM and CAM in clinical isolates and evaluated the accumulation of intrinsic macrolide resistance (AIM) and morphological changes by macrolides exposure.
Methodology. Forty-nine isolates were characterized regarding erm(41) sequevars. Sequencing data were compared to the nucleotide sequence of rrl and whiB7. The AIM MIC was performed in three reference strains and 15 isolates were randomized [each set of five isolates with M. abscessus subsp. abscessus (MAA) T28, MAA C28 and subsp. massiliense (MAM)].
Results. The 49 isolates were distributed as 24 MAA T28, 5 MAA C28 and 20 MAM. The MIC50 values to CAM at day 3 in MAA T28, C28 and MAM were 1, 0.12 and 0.12 µg ml−1, while those at day 14 were 32, 0.5 and 0.12 µg ml−1, respectively. The AZM-MIC50 values at day 3 of the above isolates were 4, 0.25 and 0.5 µg ml−1, while those at day 14 were >64, 0.5 and 0.5 µg ml−1, respectively. Neither mutations in rrl of MAA T28 with acquired resistance nor deletions in whiB7 of MAA T28 without inducible resistance were observed . For AIM MIC, MAA T28 showed that the time-to-detection of AZM resistance was significantly faster over that of CAM (P<0.05). Morphological changes were not determined in all isolates.
Conclusion. Our findings did not support the suggestion for the preferential use of AZM for, at least, MAA T28 disease due to the high-level MIC value and the increased AIM. The long duration of AZM-based treatment eventually may favour the emergence of isolates with a high-level of intrinsic resistance.
NashKA,
Brown-ElliottBA,
WallaceRJ.
A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae
. Antimicrob Agents Chemother2009; 53:1367–1376 [View Article][PubMed]
Brown-ElliottBA,
VasireddyS,
VasireddyR,
IakhiaevaE,
HowardST et al. Utility of sequencing the erm(41) gene in isolates of Mycobacterium abscessus subsp. abscessus with low and intermediate clarithromycin MICs. J Clin Microbiol2015; 53:1211–1215 [View Article][PubMed]
YoshidaS,
TsuyuguchiK,
SuzukiK,
TomitaM,
OkadaM et al. Further isolation of Mycobacterium abscessus subsp. abscessus and subsp. bolletii in different regions of Japan and susceptibility of these isolates to antimicrobial agents. Int J Antimicrob Agents2013; 42:226–231 [View Article][PubMed]
HaworthCS,
BanksJ,
CapstickT,
FisherAJ,
GorsuchT.
British thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax201772
WoodsGL,
WengenackNL,
LinG,
Brown-ElliottBA,
CirilloDM et al.Performance Standards for Susceptibility Testing of Mycobacteria, Nocardia spp., and Other Aerobic Actinomycetes Clinical and Laboratory Standards Institute; 2018 p M62
WoodsGL,
WengenackNL,
LinG,
Brown-ElliottBA,
CirilloDM et al.Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes Clinical Laboratory Standards Institute; 2018
YoshidaS,
TsuyuguchiK,
KobayashiT,
TomitaM,
InoueY et al. Discrepancies between the genotypes and phenotypes of clarithromycin-resistant Mycobacterium abscessus complex. Int J Tuberc Lung Dis2018; 22:413–418 [View Article][PubMed]
PryjmaM,
BurianJ,
KuchinskiK,
ThompsonCJ.
Antagonism between front-line antibiotics clarithromycin and amikacin in the treatment of Mycobacterium abscessus infections is mediated by the whiB7 gene. Antimicrob Agents Chemother2017; 61:e01353–17 [View Article][PubMed]
ChoiG-E,
ShinSJ,
WonC-J,
MinK-N,
OhT et al. Macrolide treatment for Mycobacterium abscessus and Mycobacterium massiliense infection and inducible resistance. Am J Respir Crit Care Med2012; 186:917–925 [View Article][PubMed]
BastianS,
VezirisN,
RouxA-L,
BrossierF,
GaillardJ-L et al. Assessment of clarithromycin susceptibility in strains belonging to the Mycobacterium abscessus group by erm(41) and rrl sequencing. Antimicrob Agents Chemother2011; 55:775–781 [View Article][PubMed]
van IngenJ,
BoereeMJ,
van SoolingenD,
MoutonJW.
Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria. Drug Resist Updat2012; 15:149–161 [View Article][PubMed]
KohW-J,
JeonK,
LeeNY,
KimB-J,
KookY-H et al. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus
. Am J Respir Crit Care Med2011; 183:405–410 [View Article][PubMed]
LuthraS,
RominskiA,
SanderP.
The role of antibiotic-target-modifying and antibiotic-modifying enzymes in Mycobacterium abscessus drug resistance. Front Microbiol2018; 9:2179 [View Article][PubMed]
Comparison of drug-susceptibility patterns and gene sequences associated with clarithromycin and azithromycin resistance in Mycobacterium abscessus complex isolates and evaluation of the accumulation of intrinsic macrolide resistance