Molecular basis of clarithromycin-resistance in Mycobacterium avium–intracellulare complex

Mohamed, Jamal A.; Maeda, Shingo; Nakata, Noboru; Kai, Masahiro; Fukuchi, Kunihiko; Kashiwabara, Yoshiko

doi:10.1054/tuld.1999.0227

Cited by 36 publications

(43 citation statements)

References 27 publications

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“…Domain V is also the most common binding site for antibiotics and accounts for macrolide resistance in a variety of bacteria (5,20,21). Indeed, an abundance of literature reports suggest that point mutations at either position 2058 or 2059 in the 23S rRNA gene are the most responsible for macrolide-resistant MAC strain (6,7,8,12,22,23). However, our results indicate that some of the resistance did not arise from the mutations in domain V. Given the inherent diversity in the mechanisms of pathogenicity displayed by MAC strains, it is conceivable and likely that there are other mutations that can result in the emergence of resistance.…”

Section: Discussioncontrasting

confidence: 54%

“…Some data were inconsistent with previous reports that mutations at position 2058 or 2059 of the 23S rRNA gene accounted for most of clarithromycin-resistant MAC strains (6,7,8,12). Therefore, sequence analysis of the PCR product that showed clarithromycin resistance was implemented and showed that the clarithromycin-resistant samples, except for eight mutant specimens, were WT (-gaAAag-).…”

Section: Development Of a Detection System For The Clarithromycin Rescontrasting

confidence: 52%

“…However, this investigation demonstrated no further mutants. At least one strain showing clarithromycin resistance but carrying no mutation at position 2058 or 2059 has been observed in separate reports using clinical samples (6,7,8). This implies that other underlying mechanisms causing clarithromycin resistance undoubtedly exist in MAC strains.…”

Section: Discussionmentioning

confidence: 91%

“…Therefore, management of clarithromycin-resistant MAC isolates from advanced lung NTM is an emerging concern. It is worth noting that multidrug therapy containing clarithromycin as the key drug is now a mandatory implementation to prevent resistance.Other studies have concluded that the mechanism responsible for clarithromycin-resistant MAC emergence, although it has not been fully unraveled, is point mutations in domain V of the 23S rRNA gene (6,7,8). It has been also reported that 4.0 to 10% of MAC organisms causing lung NTM are capable of acquiring clarithromycin resistance (6, 7).…”

mentioning

confidence: 99%

“…Other studies have concluded that the mechanism responsible for clarithromycin-resistant MAC emergence, although it has not been fully unraveled, is point mutations in domain V of the 23S rRNA gene (6,7,8). It has been also reported that 4.0 to 10% of MAC organisms causing lung NTM are capable of acquiring clarithromycin resistance (6, 7).…”

mentioning

confidence: 99%

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PCR-Based Rapid Identification System Using Bridged Nucleic Acids for Detection of Clarithromycin-Resistant Mycobacterium avium-M. intracellulare Complex Isolates

et al. 2016

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The nontuberculous mycobacteria (NTM) cause miscellaneous disorders in humans, especially in the lungs, which present with a variety of radiological features. To date, knowledge of the pathogenic role of the Mycobacterium avium-intracellulare complex (MAC) in the human lung and the definitive criteria for initiating multidrug therapy are still lacking. However, there is little doubt that clarithromycin is the most efficacious drug among the various treatment regimens for lung NTM. In this study, with the use of a bridged nucleic acid (BNA) probe a detection system based on a real-time PCR (BNA-PCR) for the identification of the point mutations at position 2058 or 2059 in domain V of the 23S rRNA gene responsible for clarithromycin resistance was developed and has been assessed using MAC isolates from clinical samples. Out of 199 respiratory specimens, the drug susceptibility test demonstrated 12 strains resistant to clarithromycin, while the BNA-PCR showed 8 strains carrying the point mutation at position 2058 or 2059 of the 23S rRNA gene. This system revealed that there were mycobacterial strains resistant to clarithromycin which do not carry previously identified resistance genes. This paper documents a novel system for detecting clarithromycin-resistant strains and demonstrates that although these mutations are tacitly assumed to account for >90% of the reported resistant mutants, there is a significant fraction of resistant mutants that do not harbor these mutations. Therefore, unknown mechanisms affecting clarithromycin resistance remain to be elucidated. The nontuberculous mycobacteria (NTM) are ubiquitous microorganisms found in various environments. They are capable of causing miscellaneous disorders in humans, especially in the lungs, which present with a variety of radiological features. It is noteworthy that the prevalence of lung NTM is increasing throughout the world (1, 2). Whereas NTM diversity in clinical manifestations and geographic distribution has been well documented, Mycobacterium avium and Mycobacterium intracellulare, collectively referred to as the Mycobacterium avium-intracellulare complex (MAC), are frequently isolated from such patients in most countries (3).To date, knowledge of the pathogenic role of MAC strains in the human lung and the definitive criteria for initiating multidrug therapy are still lacking. However, there is little doubt that clarithromycin is the most efficacious drug among the various treatment regimens for lung NTM. Clarithromycin is a ribosome-targeting macrolide antibiotic that interacts with a bacterial 23S rRNA hairpin-like structure in domain II and the peptidyl transferase loop in domain V (4, 5). Additionally, clarithromycin is the only agent for which susceptibility testing has high clinical efficacy. Therefore, management of clarithromycin-resistant MAC isolates from advanced lung NTM is an emerging concern. It is worth noting that multidrug therapy containing clarithromycin as the key drug is now a mandatory implementation to prevent resistance.Other s...

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Section: Discussioncontrasting

confidence: 54%

Section: Development Of a Detection System For The Clarithromycin Rescontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

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PCR-Based Rapid Identification System Using Bridged Nucleic Acids for Detection of Clarithromycin-Resistant Mycobacterium avium-M. intracellulare Complex Isolates

et al. 2016

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Isolation and characterizations of clarithromycin-resistant Mycobacterium avium clinical isolates

Lee

Park

Kim

et al. 2011

J. Clin. Lab. Anal.

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Mycobacterium avium is an important intracellular pathogen, particularly in AIDS patients. It also shows the second frequency among nontuberculous mycobacteria infections in Korea. Point mutations of domain V region of the 23S rRNA gene has been known to confer clarithromycin resistance to M. avium. In order to isolate the clarithromycin-resistant strains from clinical isolates of M. avium and characterize them, we isolated the clarithromycin-resistant strains from clinical isolates of M. avium using reverse hybridization assay (RHA) and broth microdilution test (BMT). Three clarithromycin-resistant isolates with high level of MICs were found from 274 clinical isolates by BMT. Two of three resistant strains were also found by RHA, which revealed point mutations in the domain V region of the 23S rRNA. We report here clarithromycin-resistant clinical isolates of M. avium with the different characteristics from those of the resistant strains reported from earlier studies.

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Mechanisms of Action and Resistance of Antimycobacterial Agents

Karakousis

2009

Antimicrobial Drug Resistance

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Molecular basis of clarithromycin-resistance in Mycobacterium avium–intracellulare complex

Cited by 36 publications

References 27 publications

PCR-Based Rapid Identification System Using Bridged Nucleic Acids for Detection of Clarithromycin-Resistant Mycobacterium avium-M. intracellulare Complex Isolates

PCR-Based Rapid Identification System Using Bridged Nucleic Acids for Detection of Clarithromycin-Resistant Mycobacterium avium-M. intracellulare Complex Isolates

Isolation and characterizations of clarithromycin-resistant Mycobacterium avium clinical isolates

Mechanisms of Action and Resistance of Antimycobacterial Agents

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