Positive Effect of Liposomal Amikacin for Inhalation on Mycobacterium abcessus in Cystic Fibrosis Patients

Caimmi, Davide; Martocq, Nicolas; Trioleyre, Delphine; Guinet, Catherine; Godreuil, Sylvain; Daniel, Thomas M.; Chiron, R.

doi:10.1093/ofid/ofy034

Cited by 28 publications

(20 citation statements)

References 14 publications

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“…The liposomes are taken up by lung macrophages, allowing for intracellular delivery of high levels of amikacin into nontuberculous mycobacterial cells (Rose et al 2014;Olivier et al 2017). In 2018, Caimmi et al (2018) reported the effect of LAI (590 mg daily) on five patients with Mycobacterium abscessus in cystic fibrosis. None of the five patients showed any side effects related to the treatment, while three patients showed improvement of their pulmonary function test values and their clinical symptoms.…”

Section: Amikacinmentioning

confidence: 99%

Nanomedicine review: clinical developments in liposomal applications

et al. 2019

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Background Many conventional drugs exhibit poor pharmacokinetics, limited bioavailability and a high toxicity, all of which restrain their use. To overcome these issues and improve the therapeutic indexes of the drug, the emergent fields of nanotechnology and nanomedicine have made significant progress in detection, diagnosis and treatment of several diseases at clinical level (Li et al. 2014; Yingchoncharoen et al. 2016; Signorell et al. 2018). In fact, thanks to nanoparticles and liposomes, it has been possible to decrease the toxicity and improve the pharmacokinetics parameters, such as distribution, increased circulation time, targeted controlled release, increased intracellular concentration, and

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Section: Amikacinmentioning

confidence: 99%

Nanomedicine review: clinical developments in liposomal applications

et al. 2019

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“…In a small case series, Caimmi et al described five CF patients treated with ALIS for MABS (three of whom completed therapy) and none were found to have therapy-limiting side effects. 93 CF patients may be more prone to the vestibular toxicity of inhaled amikacin due to chronic exposure to parenteral aminoglycosides to treat Pseudomonas infections. 94 In the CONVERT study, which enrolled patients with amikacin-susceptible MAC as well as sputum positivity despite at least 6 months of guideline-based therapy (GBT), 29% of patients in the ALIS-GBT arm compared with 8.9% in the GBT-only arm achieved culture conversion.…”

Section: Drugs Of Emerging Efficacy Inhaled Amikacinmentioning

confidence: 99%

Nontuberculous Mycobacteria in Cystic Fibrosis

Richards

Olivier

2019

Semin Respir Crit Care Med

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Over the past decade, the incidence of nontuberculous mycobacterial (NTM) infection has been increasing in cystic fibrosis patients. Along with this have come a host of complications and burdens to patients that threaten longevity and quality of life. The two main constituents of NTM pulmonary disease, Mycobacterium avium complex (MAC) and M. abscessus, are notoriously difficult to treat with suboptimal clinical responses and are accompanied by high treatment burdens for patients. This review aims to summarize the current knowledge of NTM epidemiology, pathogenesis, professional society guidelines for diagnosis and treatment, and the efficacy of current management recommendations, with attention to cystic fibrosis patients. We go on to examine drugs of emerging but unknown efficacy in clinical use to provide a comprehensive assessment of the current state of management of NTM for cystic fibrosis patients.

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“…Advances have been made in the area of aerosol delivery carriers and devices. The success of inhalational therapies with liposomal amikacin (Olivier et al, 2014 ; Caimmi et al, 2018 ) and Arikayce™ (Olivier et al, 2017 ) has paved the way for new therapies in this category. The development of a multicenter clinical trial network will allow more rapid enrollment in new drug treatment trials (Kevin Winthrop, personal communication).…”

Section: Introductionmentioning

confidence: 99%

Optimization and Lead Selection of Benzothiazole Amide Analogs Toward a Novel Antimycobacterial Agent

et al. 2018

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Mycobacteria remain an important problem worldwide, especially drug resistant human pathogens. Novel therapeutics are urgently needed to tackle both drug-resistant tuberculosis (TB) and difficult-to-treat infections with nontuberculous mycobacteria (NTM). Benzothiazole adamantyl amide had previously emerged as a high throughput screening hit against M. tuberculosis (Mtb) and was subsequently found to be active against NTM as well. For lead optimization, we applied an iterative process of design, synthesis and screening of several 100 analogs to improve antibacterial potency as well as physicochemical and pharmacological properties to ultimately achieve efficacy. Replacement of the adamantyl group with cyclohexyl derivatives, including bicyclic moieties, resulted in advanced lead compounds that showed excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12 μg/mL against M. abscessus (Mabs) and other rapid- growing NTM, 1–2 μg/mL against M. avium complex (MAC), and 0.12–0.5 μg/mL against Mtb. No pre-existing resistance was found in a collection of n = 54 clinical isolates of rapid-growing NTM. Unlike many antibacterial agents commonly used to treat mycobacterial infections, benzothiazole amides demonstrated bactericidal effects against both Mtb and Mabs. Metabolic labeling provided evidence that the compounds affect the transfer of mycolic acids to their cell envelope acceptors in mycobacteria. Mapping of resistance mutations pointed to the trehalose monomycolate transporter (MmpL3) as the most likely target. In vivo efficacy and tolerability of a benzothiazole amide was demonstrated in a mouse model of chronic NTM lung infection with Mabs. Once daily dosing over 4 weeks by intrapulmonary microspray administration as 5% corn oil/saline emulsion achieved statistically significant CFU reductions compared to vehicle control and non-inferiority compared to azithromycin. The benzothiazole amides hold promise for development of a novel therapeutic agent with broad antimycobacterial activity, though further work is needed to develop drug formulations for direct intrapulmonary delivery via aerosol.

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Positive Effect of Liposomal Amikacin for Inhalation on Mycobacterium abcessus in Cystic Fibrosis Patients

Cited by 28 publications

References 14 publications

Nanomedicine review: clinical developments in liposomal applications

Nanomedicine review: clinical developments in liposomal applications

Nontuberculous Mycobacteria in Cystic Fibrosis

Optimization and Lead Selection of Benzothiazole Amide Analogs Toward a Novel Antimycobacterial Agent

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