Pulmonary drug delivery systems for antimicrobial agents: facts and myths

Falagas, Matthew E.; Michalopoulos, Argyris; Metaxas, Eugenios

doi:10.1016/j.ijantimicag.2009.10.001

Cited by 10 publications

(7 citation statements)

References 45 publications

(48 reference statements)

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“…[76] However, both efficacy and toxicity need to be well defined in clinical studies before these new nebulizer devices can be used routinely for drugs such as tobramycin and colistin. [77] …”

Section: New Inhalation Formulationsmentioning

confidence: 99%

New Antimicrobial Strategies in Cystic Fibrosis

Westreenen

Tiddens

2010

Pediatric Drugs

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With more antibiotic resistance and emerging pathogens in cystic fibrosis (CF) patients, the need for new strategies in the lifelong treatment of pulmonary infection has increased. Most of the focus is on chronic infection with Pseudomonas aeruginosa, which is still thought to be the main pathogen leading to advanced CF lung disease. Other bacterial species are also recognized in the pathogenesis of CF lung disease, even though their definitive role is not well established yet. Clearly, expansion of treatment options is urgently needed. This article focuses on recent developments in the field of new antimicrobial strategies for CF. It is clear that studies on new classes of antibiotics or antimicrobial-like drugs are scarce, and that most studies involve new (inhalation) formulations, new routes of delivery, or analogs of existing classes of antibiotics. Studies of new antibiotic-like drugs are, in most cases, in preclinical phases of development and only a few of these agents may reach the market. Importantly, new inhaled antibiotics, e.g. aztreonam, levofloxacin, and fosfomycin, and new, more efficient delivery systems such as dry powder inhalation and liposomes for current antibiotics are in the clinical phase of development. These developments will be of great importance in improving effective treatment and reducing the treatment burden for CF patients in the near future.

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Section: New Inhalation Formulationsmentioning

confidence: 99%

New Antimicrobial Strategies in Cystic Fibrosis

Westreenen

Tiddens

2010

Pediatric Drugs

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“…For respiratory conditions such as lung infections, targeted delivery of drugs directly to the site of action could provide unique benefits compared to systemic administration. Local delivery to the lung could achieve a higher local concentration at the target site with reduced systemic exposure and risk of adverse events 12 . However, despite the increasing interest in pulmonary delivery over the last few decades, compared to conventional oral dosage forms, the pharmacokinetics (PK) of drug molecules after pulmonary administration remains relatively poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection

Sou

Kukavica-Ibrulj

Soukarieh

et al. 2019

Journal of Pharmaceutical Sciences

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Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.

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“…Ideally, any nebulized liquid solution should be prepared specifically for aerosol delivery, since aerosolization of intravenous preparations of antibiotics may contain chemicals in the delivery vehicle, that are irritating to the respiratory mucosa and can cause bronchospasm. No study has shown an advantage of ultrasonic, jet or vibrating mesh nebulizers in ICU patients (19, 20). Jet nebulizers generate aerosols by using compressed gas, ultrasonic nebulizers use a piezoelectric crystal to agitate a solution at high frequency, while mesh nebulizers use a high–frequency vibrating mesh to pump a solution through tapered holes (20, 21).…”

Section: Modern Aerosol Delivery Systems (Table 1)mentioning

confidence: 99%

Adjunctive Nebulized Antibiotics: What Is Their Place in ICU Infections?

Niederman

2019

Front. Med.

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Inhaled antibiotics have been used as adjunctive therapy for patients with pneumonia, primarily caused by multidrug resistant (MDR) pathogens. Most studies have been in ventilated patients, although non-ventilated patients have also been included (but not discussed in this review), and most patients have had nosocomial pneumonia. Aerosolized antibiotics are generally added to systemic therapy, and have shown efficacy, primarily as salvage therapy for failing patients and as adjunctive therapy after an MDR gram-negative has been identified. An advantage to aerosolized antibiotics is that they can achieve high intra-pulmonary concentrations that are potentially effective, even for highly resistant pathogens, and because they are generally not well-absorbed systemically, it is possible to avoid some of the toxicities of systemic therapy. When using inhaled antibiotics, it is essential to choose the appropriate agent and the optimal delivery method. Animal and human studies have shown that aerosolized antibiotics reach higher concentrations in the lung than systemic antibiotics, but that areas of dense pneumonia may not receive as much antibiotic as less affected areas of lung. Optimal delivery in ventilated patients depends on device selection, generally with a preference for vibrating mesh nebulizers and with careful attention to where the device is placed in the ventilator circuit and how the delivery is coordinated with the ventilator cycle. Although some studies have shown a benefit for clinical cure, adjunctive therapy has not led to reduced mortality. In some studies, adjunctive aerosol therapy has reduced the duration of systemic antibiotic therapy, thus serving to promote antimicrobial stewardship. Two recent multicenter, randomized, double-blinded, placebo-controlled trials of adjunctive nebulized antibiotics for VAP patients with suspected MDR gram-negative pneumonia were negative for their primary endpoints. This may have been related to trial design and execution and the lessons learned from these studies need to be incorporated in any future trials. Currently, routine use of adjunctive aerosolized therapy cannot be supported by available data, and this therapy is only recommended to assist in the eradication of highly resistant pathogens and to be used as salvage therapy for patients failing systemic therapy.

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Pulmonary drug delivery systems for antimicrobial agents: facts and myths

Cited by 10 publications

References 45 publications

New Antimicrobial Strategies in Cystic Fibrosis

New Antimicrobial Strategies in Cystic Fibrosis

Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection

Adjunctive Nebulized Antibiotics: What Is Their Place in ICU Infections?

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