Antibiotic-Nanomedicines: Facing the Challenge of Effective Treatment of Antibiotic-Resistant Respiratory Tract Infections

Ritsema, Jeffrey A. S.; Weide, Hessel van der; Welscher, Yvonne M. te; Goessens, W. H. F.; Nostrum, Cornelus F. van; Storm, Gert; Bakker-Woudenberg, Irma A. J. M.; Hays, John P.

doi:10.2217/fmb-2018-0194

Cited by 18 publications

(18 citation statements)

References 62 publications

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“…The clinical utility of many AMPs is currently limited by several implementation barriers, such as toxic side effects (8) and short biological half-lives due to susceptibility to proteases (8,9). However, these implementation barriers could potentially be offset by the development of nanomedicine formulations based on AMPs (13,19). Additionally, the direct delivery of antibiotic-nanomedicines to the lungs may provide therapeutic advantages compared with conventional administration methods (19,20).…”

Section: Discussionmentioning

confidence: 99%

“…However, these implementation barriers could potentially be offset by the development of nanomedicine formulations based on AMPs (13,19). Additionally, the direct delivery of antibiotic-nanomedicines to the lungs may provide therapeutic advantages compared with conventional administration methods (19,20). To investigate this hypothesis, the novel AMP AA139 was successfully entrapped in two nanocarriers (PNP or MCL) to generate two novel nanomedicines (AA139-PNP and AA139-MCL).…”

Section: Discussionmentioning

confidence: 99%

“…As such, the direct delivery of AMP nanomedicines to the lungs is a promising research strategy at a time when traditional antibiotics and treatment for respiratory tract infections are becoming ineffective (19,20). In this respect, the European Union's Seventh Framework Programme provided funding to the PneumoNP research consortium, with the goal of developing and investigating novel AMP nanomedicines in the treatment of pneumonia (21).…”

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confidence: 99%

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Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

Weide

Cossío

Gracia

et al. 2020

Antimicrob Agents Chemother

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Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e. AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP currently in development for the treatment of multidrug-resistant Gram-negative infections. AA139 was entrapped in polymeric nanoparticles (PNP) or lipid-core micelles (MCL). The antimicrobial activity of AA139-PNP and AA139-MCL was determined in vitro. The biodistribution and limiting doses of AA139-nanomedicines were determined in uninfected rats via endotracheal aerosolization. The early bacterial killing activity of the AA139-nanomedicines in infected lungs was assessed in a rat model of pneumonia-septicemia caused by an extended-spectrum β-lactamase-producing Klebsiella pneumoniae. In this model, the therapeutic efficacy was determined by once-daily (q24h) administration over 10 days. Both AA139-nanomedicines showed equivalent in vitro antimicrobial activities (similar to free AA139) and in uninfected rats they exhibited longer residence times in the lungs compared to free AA139 (∼20% longer for AA139-PNP and ∼80% longer for AA139-MCL), as well as reduced toxicity enabling a higher limiting dose. In rats with pneumonia-septicemia, both AA139-nanomedicines showed significantly improved therapeutic efficacy in terms of an extended rat survival time, although survival of all rats was not achieved. These results demonstrate potential advantages that can be achieved using AMP-nanoformulations. AA139-PNP and AA139-MCL may be promising novel therapeutic agents for the treatment of patients suffering from multidrug-resistant Gram-negative pneumonia-septicemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

Weide

Cossío

Gracia

et al. 2020

Antimicrob Agents Chemother

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“…Nebulisers are the most used device to deliver liposomes in aerosolised droplets at the correct size [80,92]. Increasing target localisation provides options to maximise efficacy at lower drug doses, prevent the systemic degradation of antibiotics and protect them from pulmonary clearance [79,83,[112][113][114].…”

Section: Inhaled Liposomal Drug Delivery In Research and Clinical Practicementioning

confidence: 99%

Liposomal drug delivery to manage nontuberculous mycobacterial pulmonary disease and other chronic lung infections

Chalmers

Ingen

Laan³

et al. 2021

Eur Respir Rev

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Nontuberculous mycobacterial (NTM) pulmonary disease is a chronic respiratory infection associated with declining lung function, radiological deterioration and significantly increased morbidity and mortality. Patients often have underlying lung conditions, particularly bronchiectasis and COPD. NTM pulmonary disease is difficult to treat because mycobacteria can evade host defences and antimicrobial therapy through extracellular persistence in biofilms and sequestration into macrophages. Management of NTM pulmonary disease remains challenging and outcomes are often poor, partly due to limited penetration of antibiotics into intracellular spaces and biofilms. Efficient drug delivery to the site of infection is therefore a key objective of treatment, but there is high variability in lung penetration by antibiotics. Inhalation is the most direct route of delivery and has demonstrated increased efficacy of antibiotics like amikacin compared with systemic administration. Liposomes are small, artificial, enclosed spherical vesicles, in which drug molecules can be encapsulated to provide controlled release, with potentially improved pharmacokinetics and reduced toxicity. They are especially useful for drugs where penetration of cell membranes is essential. Inhaled delivery of liposomal drug solutions can therefore facilitate direct access to macrophages in the lung where the infecting NTM may reside. A range of liposomal drugs are currently being evaluated in respiratory diseases.

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“…A smaller proportion is administered by dermal or oral routes (Fornaguera & Garcia‐Celma, 2017). The inhalation route is also being explored for NMPs, for example, antibiotics‐nanomedicine for respiratory tract infections (Ritsema et al, 2018) and nanoparticle‐aided radiotherapy for lung cancer (Ngwa, Kumar, Moreau, Dabney, & Herman, 2017).…”

Section: Proposed Regulatory Immunotoxicity Evaluation Of Nmpsmentioning

confidence: 99%

Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls

Giannakou¹,

Park²,

Bosselaers

et al. 2020

WIREs Nanomed Nanobiotechnol

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Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 “Immunotoxicity Studies for Human Pharmaceuticals” of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH‐S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH‐S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

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Antibiotic-Nanomedicines: Facing the Challenge of Effective Treatment of Antibiotic-Resistant Respiratory Tract Infections

Cited by 18 publications

References 62 publications

Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

Liposomal drug delivery to manage nontuberculous mycobacterial pulmonary disease and other chronic lung infections

Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls

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