Abstract
Objectives Clarithromycin is recommended as the core agent for treating M. abscessus infections, which usually calls for at least one year of treatment course, facilitating the development of resistance. This study aimed to identify the underlying mechanism of in vivo development of clarithromycin resistance in M. abscessus clinical isolates. Methods M. abscessus isolates from patients with lung infections during long-term antibiotic therapy were longitudinally collected and sequenced. PFGE DNA fingerprinting was used to confirm the genetic relationships of the isolates. Whole genome comparative analysis was performed to identify the genetic determinants that confer the clarithromycin resistance. Results Three pairs of initially clarithromycin-susceptible and subsequently clarithromycin-resistant M. abscessus isolates were obtained. We found that the clarithromycin-resistant isolates emerged relatively rapidly, after 4–16 months of antibiotic therapy. PFGE DNA fingerprinting showed that the clarithromycin-resistant isolates were identical to the initial clarithromycin-susceptible ones. Whole genome sequencing and bioinformatics analysis identified several genetic alternations in clarithromycin-resistant isolates, including genes encoding efflux pump/transporter, integral component of membrane, and the tetR and lysR family transcriptional regulators. Conclusion We identified genes likely encoding new factors contributing to clarithromycin-resistance phenotype of M. abscessus, which can be useful in prediction of clarithromycin resistance in M. abscessus.
Highlights
Nontuberculous mycobacteria (NTM) refer to mycobacterial species other than those of Mycobacterium tuberculosis complex and Mycobacterium leprae [1]
M. abscessus isolates that were initially clarithromycin susceptible and acquired clarithromycin resistance from a same patient were isolated from three patients during the study period
As the three cases had initial positive AFB smears, all of them received multidrug combinations of antituberculosis treatment before the diagnosis of M. abscessus lung disease. ough the patients were given a continuation of long-term multitherapy, their symptoms and radiological results were not improved
Summary
Nontuberculous mycobacteria (NTM) refer to mycobacterial species other than those of Mycobacterium tuberculosis complex and Mycobacterium leprae [1]. It has been increasingly recognized that NTM are important human pathogens causing distinct infections with clinical manifestations similar to tuberculosis, such as chronic pulmonary disease, cutaneous disease, lymphadenitis, and disseminated disease [1]. Mycobacterium avium complex, in NTM lung disease, and is increasing in incidence [3]. As M. abscessus is intrinsically resistant to multiple antibiotic classes, treatment of infections caused by M. abscessus is infamously difficult [5]. No reliable antibiotic regimen has been established for M. abscessus pulmonary disease. The cure rate for M. abscessus lung disease is Canadian Respiratory Journal low (about 30–50%), and the recurrence rate is high, even after successful treatment completion [6, 7]
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