Clinical experimentation with aerosol antibiotics: current and future methods of administration

Zarogoulidis, Paul; Kioumis, Ioannis; Porpodis, Κonstantinos; Spyratos, Dionysios; Tsakiridis, Kosmas; Huang, Haidong; Li, Qiang; Turner, J. Francis; Browning, Robert; Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Konstantinos

doi:10.2147/dddt.s51303

Cited by 25 publications

(26 citation statements)

References 138 publications

(144 reference statements)

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“…The inflammatory profile in the airways, in particular, the neutrophil burden and the concentrations of chemokines and cytokines such as CXCL1/KC, CXCL2/MIP-2 and CCL2/JE, was reduced in mice treated with POL7001, suggesting a positive impact of this treatment on the pulmonary physiology. The administration of antibiotics by the inhaled route is widely adopted in patients with CF and bronchiectasis (31) and has recently been tested for the treatment of pneumonia, including VAP (32). Advantages of inhaled administration include higher efficacy due to high local concentrations and fewer side effects due to low systemic exposure of the drug.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia

Cigana

Bernardini

Facchini

et al. 2016

Antimicrob Agents Chemother

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The clinical development of antibiotics with a new mode of action combined with efficient pulmonary drug delivery is a priority against untreatable Pseudomonas aeruginosa lung infections. POL7001 is a macrocycle antibiotic belonging to the novel class of protein epitope mimetic (PEM) molecules with selective and potent activity against P. aeruginosa. We investigated ventilatorassociated pneumonia (VAP) and cystic fibrosis (CF) as indications of the clinical potential of POL7001 to treat P. aeruginosa pulmonary infections. MICs of POL7001 and comparators were measured for reference and clinical P. aeruginosa strains. The therapeutic efficacy of POL7001 given by pulmonary administration was evaluated in murine models of P. aeruginosa acute and chronic pneumonia. POL7001 showed potent in vitro activity against a large panel of P. aeruginosa isolates from CF patients, including multidrug-resistant (MDR) isolates with adaptive phenotypes such as mucoid or hypermutable phenotypes. The efficacy of POL7001 was demonstrated in both wild-type and CF mice. In addition to a reduced bacterial burden in the lung, POL7001-treated mice showed progressive body weight recovery and reduced levels of inflammatory markers, indicating an improvement in general condition. Pharmacokinetic studies indicated that POL7001 reached significant concentrations in the lung after pulmonary administration, with low systemic exposure. These results support the further evaluation of POL7001 as a novel therapeutic agent for the treatment of P. aeruginosa pulmonary infections. Pseudomonas aeruginosa is a difficult-to-treat human pathogen causing a wide range of infections, especially in the respiratory tract. These infections, such as ventilator-associated pneumonia (VAP), are often life-threatening. Cystic fibrosis (CF) is another disease where P. aeruginosa lung infections are associated with worse outcomes (1). The high prevalence of P. aeruginosa infections, in nearly 80% of CF patients Ͼ18 years of age (2), is partially due to the propensity of this species to form biofilms and cause chronic infection.Frequently observed inefficacy of available treatments is due to intrinsic or acquired resistance of P. aeruginosa and/or limited penetration of antibiotics into biofilms (3). However, despite the need for new drugs, only few novel antipseudomonal drugs or modifications of existing molecules are currently in the late stage of preclinical or clinical development (4). A new family of potent protein epitope mimetic (PEM) antibiotics has recently been described. These molecules show selective activity against P. aeruginosa by inhibiting the transport of the lipopolysaccharide to the outer membrane (5). Among these antibiotics, we showed that POL7001 provided protection against lethal P. aeruginosa infection in a mouse septicemia model (5).In this work, to investigate the efficacy of POL7001 in models relevant for VAP or CF, we used murine P. aeruginosa acute and chronic pneumonia, including in CF mice. We report that pulmonary delivery of POL7001 is e...

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Section: Discussionmentioning

confidence: 99%

Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia

Cigana

Bernardini

Facchini

et al. 2016

Antimicrob Agents Chemother

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“…Several antibiotic compounds were introduced in the market along with a specific device that was appropriate to deliver more efficiently the powder or aerosol by inhalation [2]. The following antibiotics are already on the market or have been investigated for aerosol administration; Tobramycin, Aztreonam, Gentamicin, Amikacin, Fosfomycin, Clolistin, Amphotericin, Isoniasid, Rifampicin, Capreomycin, Levofloxacin, Ciprofloxacin, Doxycycline, Clindamycin and Telithromycin.…”

Section: Antibioticsmentioning

confidence: 99%

“…The following antibiotics are already on the market or have been investigated for aerosol administration; Tobramycin, Aztreonam, Gentamicin, Amikacin, Fosfomycin, Clolistin, Amphotericin, Isoniasid, Rifampicin, Capreomycin, Levofloxacin, Ciprofloxacin, Doxycycline, Clindamycin and Telithromycin. Several of the antibiotics were administered in their raw form or as a novel compound in order to enhance the absorption [2]. The different methods of the aerosol administration can be found on Table 1 [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47].…”

Section: Antibioticsmentioning

confidence: 99%

“…It is very well known that for asthma and chronic obstructive disease (COPD) we use nebulisers, metered dose inhalers (MDIs), and dry powder inhalers (DPIs) for the delivery of inhalational bronchodilators and corticosteroids [1]. Moreover; there are inhaled antibiotics and inhaled drugs for pulmonary hypertension already on the market [2,3]. It is known that there are several factors affecting the distribution and absorption of an inhalational compound.…”

Section: Introductionmentioning

confidence: 99%

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Drug development of Lung Diseases by way of Drug Repurposing; What a Pulmonary Physician can do in the Laboratory

Tsiouda¹,

Hohenforst-Schmidt²,

Sardeli³

et al. 2018

J. Biomed

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Lung diseases are very common among several patients such as; asthma, chronic obstructive pulmonary disease, lung cancer, cystic fibrosis and pulmonary fibrosis. In many of these diseases we already have inhalation therapies, however; for others we have only systematic administration. There are also diseases of the lung that cause pulmonary hypertension and architectural damage to the lung such as; emphysema and bronchiectasis. Several of the drugs currently administered intravenously are being investigated whether they could be transformed and delivered as aerosol therapy. We will present the methodology that can be used and has been used for several drugs.

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“…The knowledge gained from inhaled insulin indicates that an underlying respiratory disease/exacerbation of this disease or respiratory tract infection changes the systemic absorption of an aerosol-administered drug 23. In recent years, extensive investigation with inhaled antibiotics has been performed, and there are already several products on the market 6,7. Moreover; experimentation has been made to enhance aerosol drug delivery 26.…”

Section: Introductionmentioning

confidence: 99%

Optimization of nebulized delivery of linezolid, daptomycin, and vancomycin aerosol

Kioumis¹,

Lampaki²,

Organtzis³

et al. 2014

DDDT

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BackgroundAt this time, several antibiotics have been investigated as possibilities for aerosol administration, but local therapy has been found to be more efficient in several diseases.Materials and methodsThe drugs linezolid (Zyvox), vancomycin (Voncon), and daptomycin (Cubicin) were tested with three jet nebulizers with seven different residual cups and different loadings. Moreover, three ultrasound nebulizers were again tested with these drugs, with different loadings and mouthpiece attachments.ResultsWhen drugs are combined with particular cup designs, they significantly lower the droplet size to 1.60 and 1.80 μm, which represents the best combination of Zyvox and cup G and Cubicin and cup D, respectively. Cup design D is suggested as the most effective cup for lowering the droplet size (2.30 μm) when considering a higher loading level (8 mL).ConclusionModification of current drugs from dry powder to solution is possible, and the residual cup design plays the most important role in droplet size production when the nebulization systems have the same properties.

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Clinical experimentation with aerosol antibiotics: current and future methods of administration

Cited by 25 publications

References 138 publications

Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia

Efficacy of the Novel Antibiotic POL7001 in Preclinical Models of Pseudomonas aeruginosa Pneumonia

Drug development of Lung Diseases by way of Drug Repurposing; What a Pulmonary Physician can do in the Laboratory

Optimization of nebulized delivery of linezolid, daptomycin, and vancomycin aerosol

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