Drug Delivery for tuberculosis: is Inhaled Therapy the Key to success?

Abstract

" The questions on the utility of inhaled TB therapy are still open-ended, but in a world where the risk of untreatable infections is ever-present, the need for continued research into TB, perhaps focusing on 'game changers' such as inhaled therapies, are of utmost importance. " Drug delivery for tuberculosisWorldwide, tuberculosis (TB) has 86% treatment success rate in new cases, leaving more than 1 million new patients without a cure [1]. Thus, the need for both shorter treatment regimens and new antibiotics is great. Current oral or injectable standard anti-TB drug regiments are well established and relatively inexpensive therapies. Still, it is evident from the rise of multidrug resistance TB (MDR-TB) worldwide, that among other factors, these approaches are not preferred among patients and healthcare professionals and, have been proven to have varying degrees of success.In the past few years there has been an enormous interest in developing more effective anti-TB vaccines [2,3], developing new anti-TB drugs that shortens treatment and exploiting the genome to accelerate the diagnosis and treatment of drug-resistant TB [4,5]. Importantly, there has also been a rising interest in developing anti-TB therapies via inhalation [6,7]. This is because, used as primary or adjunct to the current standard therapy for TB, inhaled therapy may hold the key as a potential new delivery mode that has improved health benefits. These are likely to include reduced treatment times and possibly limited insurgence of drug resistance. Specifically, for inhaled TB treatment, drugs should target alveolar macrophages that harbor microorganisms and/or maintain high drug concentration at the infection site in the lung [8]. Inhaled drug delivery offers this prospect and has the potential to achieve high concentrations of pharmacologic agents in the lungs, while producing adequate systemic concentrations through alveolar-capillary absorption to treat extrapulmonary sites of infection. It would seem that a localized delivery method would be intuitively attractive for a disease that is very often restricted, but not limited, to the lung. Inhalation therapy for TBInhalation therapy for TB is not a 'new' approach and began in the late 1940s when streptomycin started showing signs of resistance [9]. Since then, many different formulation approaches have been investigated. Micro [10,11], nanoparticles [12,13], liposomes [14], in situ forming liposomes [15], proliposomes [16,17] and liposphere [18], with single [19,20] and combination drugs [21,22], have all been manufactured with different degrees of success, although mostly limited to data collected in vitro or from preclinical studies where, for the majority, formulations were found effective in reducing bacterial counts. Nevertheless, there is no completed clinical study and it is difficult to identify which system would be the most advantageous to take further.Recent setbacks have also hindered research advances in this field, that is, the suspension of enrolment in STAND (Phase III combi...

Measuring and reporting treatment adherence: What can we learn by comparing two respiratory conditions?

“…Guidelines to overcoming barriers to DOT could be translated from TB to asthma to develop systems‐level approaches to improve adherence in those with the highest likelihood of non‐adherence to such treatments. Similarly, if continued efforts to develop inhalation TB therapies 141 are fruitful, delivery vehicles could be designed using the knowledge of common asthma inhaler technique errors.…”

Developing inhaled protein therapeutics for lung diseases

“…At 24 h post-dose, the fold difference between PEGylated and unPEGylated 80 × 320 nm, 1.5 μm, and 6 μm particles in bronchioalveolar lavage fluid (BALF), was 1.5, 3.4 and 3.7 respectively [ 103 ]. On the other hand, drug-loaded particles may be advantageous for anti-tuberculosis drugs as efficient uptake of drugs into alveolar macrophages could potentially enhance the drug’s efficacy to kill the parasitic Mycobacterium tuberculosis that hide inside the cells [ 104 ].…”

Inhaled Liposomal Antimicrobial Delivery in Lung Infections

“…Use of nebulized antibiotics for tuberculous (TB) or nontuberculous mycobacterial (NTM) infections remains a very active area of research. Inhaled antibiotics for TB and NTM have the potential to reduce dosage (up to ten times less used for the standard oral treatment of care), to limit side effects, and to result in higher drug concentrations, potentially overcoming drug resistance [32]. Liposomal formulations have the ability to be more readily and effectively phagocytosed by alveolar macrophages within the airways and alveoli, with in vitro and in vivo therapeutic advantages for TB and NTM treatment [32,33].…”