The role of amikacin in the treatment of nontuberculous mycobacterial disease

Raaijmakers, Jelmer; Schildkraut, Jodie A.; Hoefsloot, Wouter

doi:10.1080/14656566.2021.1953472

Cited by 17 publications

(13 citation statements)

References 99 publications

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“…The NADH dehydrogenase encoded by nuo(A-N) contributes to the proton-motive force in the electron transport chain ( 16 ). Because a proton-motive force is necessary for passive diffusion of molecules into the intracellular space, the decrease in nuo(A-N) expression may also contribute to increased tolerance to aminoglycosides, as their uptake has previously been shown to be dependent on proton-motive force ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

RNA Sequencing Elucidates Drug-Specific Mechanisms of Antibiotic Tolerance and Resistance in Mycobacterium abscessus

Schildkraut

Coolen

Burbaud

et al. 2022

Antimicrob Agents Chemother

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Mycobacterium abscessus is an opportunistic pathogen notorious for its resistance to most classes of antibiotics and low cure rates. M. abscessus carries an array of mostly unexplored defence mechanisms. A deeper understanding of antibiotic resistance and tolerance mechanisms is pivotal in development of targeted therapeutic regimens. We provide the first description of all major transcriptional mechanisms of tolerance to all antibiotics recommended in current guidelines, using RNA sequencing-guided experiments. M. abscessus ATCC 19977 bacteria were subjected to sub-inhibitory concentrations of clarithromycin, amikacin, tigecycline, cefoxitin and clofazimine for 4- and 24-hours, followed by RNA sequencing. To confirm key mechanisms of tolerance suggested by transcriptomic responses, we performed time-kill kinetic analysis using bacteria after pre-exposure to clarithromycin, amikacin or tigecycline for 24-hours and we constructed isogenic knockout and knockdown strains. To assess strain specificity, pan-genome analysis of 35 strains from all three subspecies was performed. Mycobacterium abscessus shows both drug-specific and common transcriptomic responses to antibiotic exposure. Ribosome-targeting antibiotics clarithromycin, amikacin and tigecycline elicit a common response characterized by upregulation of ribosome structural genes, the WhiB7 regulon and transferases, accompanied by downregulation of respiration through NuoA-N. Exposure to any of these drugs decreases susceptibility to ribosome-targeting drugs from multiple classes. The cytochrome bd-type quinol oxidase contributes to clofazimine tolerance in M. abscessus and the sigma factor sigH but not anti-sigma factor MAB_3542c is involved in tigecycline resistance. The observed transcriptomic responses are not strain-specific, as all genes involved in tolerance, except erm(41), are found in all included strains.

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Section: Discussionmentioning

confidence: 99%

RNA Sequencing Elucidates Drug-Specific Mechanisms of Antibiotic Tolerance and Resistance in Mycobacterium abscessus

Schildkraut

Coolen

Burbaud

et al. 2022

Antimicrob Agents Chemother

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“…However, systemic administration of amikacin is limited for prolonged use by the emergence of ototoxicity, vestibular toxicity, and renal toxicity, and the correlation between clinical outcomes and MIC is not well established [ 64 ]. Similarly, systemic penetration of antibiotics to the lung, including amikacin, is limited [ 76 ] requiring increased dosing in order to achieve effective lung concentration [ 77 ], which can lead to an increased risk of serious adverse events [ 78 ]. Many patients cannot safely reach high enough concentrations for optimal efficacy and are at risk of treatment failure [ 78 ].…”

Section: Methodsmentioning

confidence: 99%

Meeting the challenges of NTM-PD from the perspective of the organism and the disease process: innovations in drug development and delivery

Laan¹,

Snabilié²,

Obradović³

2022

Respir Res

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Non-tuberculous mycobacterial pulmonary disease (NTM-PD) poses a substantial patient, healthcare, and economic burden. Managing NTM-PD remains challenging, and factors contributing to this include morphological, species, and patient characteristics as well as the treatment itself. This narrative review focusses on the challenges of NTM-PD from the perspective of the organism and the disease process. Morphological characteristics of non-tuberculous mycobacteria (NTM), antimicrobial resistance mechanisms, and an ability to evade host defences reduce NTM susceptibility to many antibiotics. Resistance to antibiotics, particularly macrolides, is of concern, and is associated with high mortality rates in patients with NTM-PD. New therapies are desperately needed to overcome these hurdles and improve treatment outcomes in NTM-PD. Amikacin liposome inhalation suspension (ALIS) is the first therapy specifically developed to treat refractory NTM-PD caused by Mycobacterium avium complex (MAC) and is approved in the US, EU and Japan. It provides targeted delivery to the lung and effective penetration of macrophages and biofilms and has demonstrated efficacy in treating refractory MAC pulmonary disease (MAC-PD) in the Phase III CONVERT study. Several other therapies are currently being developed including vaccination, bacteriophage therapy, and optimising host defences. Newly developed antibiotics have shown potential activity against NTM-PD and include benzimidazole, delamanid, and pretomanid. Antibiotics commonly used to treat other infections have also been repurposed for NTM-PD, including clofazimine and bedaquiline. Data from larger-scale studies are needed to determine the potential of many of these therapies for treating NTM-PD.

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“…Acetyltransferase inactivates aminoglycosides and plays a significant role in acquired and intrinsic resistance to these agents in NTM infections similar to other bacteria [ 20 ]. In addition, aminoglycoside phosphotransferases are expressed by some resistant NTM species, including M. fortuitum , M. abscessus , and M. avium [ 62 ]. Nevertheless, some evaluations indicated that resistance by aminoglycoside phosphotransferases is likely to be unusual for most NTM species [ 20 ].…”

Section: Importance Of Antimicrobial Resistance Mechanisms Of Ntm Spe...mentioning

confidence: 99%

Nontuberculous Mycobacterial Resistance to Antibiotics and Disinfectants: Challenges Still Ahead

Tarashi

Siadat

Fateh

2022

BioMed Research International

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The mortality incidence from nontuberculous mycobacteria (NTM) infections has been steadily developing globally. These bacterial agents were once thought to be innocent environmental saprophytic that are only dangerous to patients with defective lungs or the immunosuppressed. Nevertheless, the emergence of highly resistant NTM to different antibiotics and disinfectants increased the importance of these agents in the health system. Currently, NTM frequently infect seemingly immunocompetent individuals at rising rates. This is of concern as the resistant NTM are difficult to control and treat. The details behind this NTM development are only beginning to be clarified. The current study will provide an overview of the most important NTM resistance mechanisms to not only antibiotics but also the most commonly used disinfectants. Such evaluations can open new doors to improving control strategies and reducing the risk of NTM infection. Moreover, further studies are crucial to uncover this association.

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The role of amikacin in the treatment of nontuberculous mycobacterial disease

Cited by 17 publications

References 99 publications

RNA Sequencing Elucidates Drug-Specific Mechanisms of Antibiotic Tolerance and Resistance in Mycobacterium abscessus

RNA Sequencing Elucidates Drug-Specific Mechanisms of Antibiotic Tolerance and Resistance in Mycobacterium abscessus

Meeting the challenges of NTM-PD from the perspective of the organism and the disease process: innovations in drug development and delivery

Nontuberculous Mycobacterial Resistance to Antibiotics and Disinfectants: Challenges Still Ahead

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