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Prevalence of Drug Resistance Mutations in Clinical and Environmental Nontuberculous Mycobacteria Isolates in the US
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A7705 - Prevalence of Drug Resistance Mutations in Clinical and Environmental Nontuberculous Mycobacteria Isolates in the US
Author Block: R. Davidson1, S. Kammlade1, S. E. Nick1, R. R. Rodger2, E. Epperson1, N. A. Hasan1, C. L. Daley3, J. A. Nick3, M. Strong1, J. R. Honda1, M. Salfinger2; 1Center for Genes, Environment and Health, National Jewish Health, Denver, CO, United States, 2Mycobacteriology, National Jewish Health, Denver, CO, United States, 3Department of Medicine, National Jewish Health, Denver, CO, United States.
RATIONALE
Nontuberculous mycobacteria (NTM) cause pulmonary and extrapulmonary infections and are difficult to treat due to innate resistance to many antibiotics. A few of the effective drugs against NTM include the aminoglycoside: amikacin (AMK), and the macrolides: azithromycin (AZM) and clarithromycin (CLR). Though drug resistance (DR) mutations have been observed previously in NTM, their prevalence has not been widely reported for clinical and environmental isolates in the United States (US). Understanding DR genotypes and their relationships to antimicrobial susceptibility test (AST) results could improve antibiotic choices and treatment outcomes.
METHODS
All US isolates in the NTM Genomic Database at National Jewish Health (n=440) including six clinically relevant NTM species were screened for DR mutations in the 16S ribosomal RNA (rRNA) and 23S rRNA genes corresponding to amikacin and macrolide resistance, respectively. An additional mutation in the erm(41) gene controlling inducible macrolide resistance was studied only in M. abscessus isolates with full-length genes (n=137). For a subset of isolates (n=82), ASTs for AMK, AZM and CLR were performed, and minimum inhibitory concentrations (MIC) were associated with DR genotypes.
RESULTS
We evaluated 383 (80%) clinical and 87 (20%) environmental isolates from over 23 US states including six species and subspecies: M. chimaera (33%), M. abscessus ssp. abscessus (32%), M. abscessus ssp. massiliense (17%), M. avium (12%), M. intracellulare (6%) and M. chelonae (1%). DR mutations in the 16S rRNA at position 1408, corresponding to amikacin resistance, were found in 4.9% of isolates and four of six NTM species. DR mutations in the 23S rRNA at positions 2058 and/or 2059, which confer macrolide resistance, were observed in 5.4% of isolates and five of six species. Interestingly, DR mutations in rRNA genes were found only in clinical and not environmental isolates. Of the isolates with AST results, the 16S rRNA mutation corresponded to AMK MICs values >64 mcg/mL, and 23S rRNA mutations resulted in AZM MICs >256 mcg/mL and CLR MICs >32 mcg/mL. For M. abscessus isolates with full-length erm(41) genes, 12% had loss-of-function mutations at position 28 which abolish the inducible macrolide resistance phenotype.
CONCLUSIONS
DR mutations in the 16S and 23S rRNAs are present in low frequencies (~5%) in clinical NTM populations, but are not found in environmental isolates, suggesting that DR genotypes may be selected for in patients exposed to antibiotic treatment. As many as 12% of M. abscessus are susceptible to macrolides despite the presence of full-length erm(41) genes.
Author Block: R. Davidson1, S. Kammlade1, S. E. Nick1, R. R. Rodger2, E. Epperson1, N. A. Hasan1, C. L. Daley3, J. A. Nick3, M. Strong1, J. R. Honda1, M. Salfinger2; 1Center for Genes, Environment and Health, National Jewish Health, Denver, CO, United States, 2Mycobacteriology, National Jewish Health, Denver, CO, United States, 3Department of Medicine, National Jewish Health, Denver, CO, United States.
RATIONALE
Nontuberculous mycobacteria (NTM) cause pulmonary and extrapulmonary infections and are difficult to treat due to innate resistance to many antibiotics. A few of the effective drugs against NTM include the aminoglycoside: amikacin (AMK), and the macrolides: azithromycin (AZM) and clarithromycin (CLR). Though drug resistance (DR) mutations have been observed previously in NTM, their prevalence has not been widely reported for clinical and environmental isolates in the United States (US). Understanding DR genotypes and their relationships to antimicrobial susceptibility test (AST) results could improve antibiotic choices and treatment outcomes.
METHODS
All US isolates in the NTM Genomic Database at National Jewish Health (n=440) including six clinically relevant NTM species were screened for DR mutations in the 16S ribosomal RNA (rRNA) and 23S rRNA genes corresponding to amikacin and macrolide resistance, respectively. An additional mutation in the erm(41) gene controlling inducible macrolide resistance was studied only in M. abscessus isolates with full-length genes (n=137). For a subset of isolates (n=82), ASTs for AMK, AZM and CLR were performed, and minimum inhibitory concentrations (MIC) were associated with DR genotypes.
RESULTS
We evaluated 383 (80%) clinical and 87 (20%) environmental isolates from over 23 US states including six species and subspecies: M. chimaera (33%), M. abscessus ssp. abscessus (32%), M. abscessus ssp. massiliense (17%), M. avium (12%), M. intracellulare (6%) and M. chelonae (1%). DR mutations in the 16S rRNA at position 1408, corresponding to amikacin resistance, were found in 4.9% of isolates and four of six NTM species. DR mutations in the 23S rRNA at positions 2058 and/or 2059, which confer macrolide resistance, were observed in 5.4% of isolates and five of six species. Interestingly, DR mutations in rRNA genes were found only in clinical and not environmental isolates. Of the isolates with AST results, the 16S rRNA mutation corresponded to AMK MICs values >64 mcg/mL, and 23S rRNA mutations resulted in AZM MICs >256 mcg/mL and CLR MICs >32 mcg/mL. For M. abscessus isolates with full-length erm(41) genes, 12% had loss-of-function mutations at position 28 which abolish the inducible macrolide resistance phenotype.
CONCLUSIONS
DR mutations in the 16S and 23S rRNAs are present in low frequencies (~5%) in clinical NTM populations, but are not found in environmental isolates, suggesting that DR genotypes may be selected for in patients exposed to antibiotic treatment. As many as 12% of M. abscessus are susceptible to macrolides despite the presence of full-length erm(41) genes.
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