10 November 2022

Article by Dave Griffin

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For respiratory tract infections, delivering an antimicrobial directly to the lung is a logical means of both maximizing drug concentrations at the site of infection and limiting the potential for systemic adverse effects [1]. This route of administration has been used to treat chronic airway infections since the 1940s but much of the earliest experience was with the aerosolization of antibiotics designed for parenteral administration. Because they were not physiologically compatible, and contained added preservatives, these early formulations frequently irritated the respiratory tract [2]. In the late 1990s, this all changed with the development of a tobramycin treatment designed specifically for inhalation to treat chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) [2]. Since that time, however, only nebulized and dry powder forms of tobramycin and colistin, and nebulized aztreonam, have been approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for CF [2, 3], and a liposomal formulation of amikacin has been approved by both the EMA and FDA for non-tuberculous mycobacterial (NTM) lung infections caused by Mycobacterium avium Complex (MAC) in adults with limited treatment options [4, 5].

With the increasing incidence of respiratory infections caused by multidrug-resistant (MDR) pathogens, the limited availability of inhaled antimicrobials and approved indications, despite being generally discouraged by many specialists, has led to the inhaled administration of intravenous (IV) antibiotics [6]. Such “off-label” use includes nebulization of the injectable formulations of amikacin, amphotericin, ceftazidime, gentamicin, and tobramycin to manage non-CF bronchiectasis, MDR NTM infections, and ventilator-associated bacterial pneumonia [2, 7].

This “off-label” usage clearly shows the considerable interest by treating physicians for the development of inhaled antibiotics, especially for the treatment of lower respiratory tract infections other than CF. However, both the science behind, and development of, such agents is complex owing to the various interactions and factors that need to be considered (Figure 1) including:
•    The potency of the antimicrobial which effects its ability to exert its antimicrobial effect on the infecting pathogen (Pharmacodynamics [PD])
•    The pharmacokinetic properties of the agent and its safety profile (PK/Safety)
•    The physicochemical properties of the drug substance (e.g., its solubility profile, particle size, morphology, and density) which determines the formulation development (Feasibility)
•    The type of formulation (e.g., dry powder, propellant-driven liquid, or aqueous inhalation formulation) selected to deliver the drug as this affects the device to be used (Compatibility) and the avoidance of side-effects (Tolerability), and
•    The device to be used as this affects compatibility with the targeted patient population (Usability).

Figure 1    Interactions and considerations in the development of inhaled antimicrobials

Developing antimicrobials for inhalational use

Inhaled antibiotics need to be developed to optimize delivery to the lung, but this often requires modification of the drug’s properties to enhance lung deposition. The formulation then needs to be paired with an appropriate inhaler or nebulizer to ensure that the particle size will be adequate for distribution within the lung and to ensure dose consistency [6]. Guidelines on the development of the various inhalation drug products have been published by both the EMA and the FDA [8-10].

Assuming an appropriate formulation can be achieved, a battery of preclinical safety and toxicity studies need to be conducted before clinical trials can commence and both EMA and FDA guidelines are available to assist the developer [11, 12].

To obtain approval for marketing, clinical trials of an appropriate design need to be conducted to demonstrate both efficacy and safety in the target population. This can be a challenge as several factors need to be considered such as (but not restricted to):
•    Selecting the appropriate population for the indication to be sought and ensuring an adequate number of subjects can be enrolled into that study
•    Ensuring the comparator is both appropriate and acceptable to all participating study centres and ultimately, all countries in which marketing approval will be sought
•    Whether to administer the agent as a stand-alone treatment or whether to administer it as an add-on treatment to the current standard of care treatment(s)
•    Selecting the most suitable efficacy endpoint and ensuring the magnitude of effect is acceptable to the regulatory authorities.

Defining treatment success can be particularly challenging since this will depend on selecting or designing an appropriate clinical endpoint (e.g., improvement of forced expiratory volume in 1 second [FEV1]) and, preferably, also a microbiological endpoint (e.g., a reduction in bacterial counts or bacterial eradication) [13]. A recent example illustrates this difficulty where inhaled amikacin as adjunctive therapy to standard-of-care IV therapy in mechanically ventilated patients with Gram-negative pneumonia failed to show a difference in the FDA-required primary endpoint of all-cause mortality evaluated at a fixed time point between day 14 and day 28 [14, 15]. Obtaining scientific advice from regulators, particularly the EMA and the FDA, is critical and will likely improve the probability of a successful outcome.

The microbiological aspects of developing antibiotics for inhalation differs in several ways to that for systemic treatments. If the antibiotic is a new or unapproved entity, in vitro and in vivo studies still need to be conducted to characterize the agent’s antimicrobial activity to provide confidence in its potential clinical utility. However, unlike for systemic agents where dose-fractionation studies in animal infection models are commonly used to determine the PK/PD index and target that are used to select the dosing regimen for clinical trials, the relationships between dose and effect in animals with inhaled antimicrobial agents has yet to be established [13]. Furthermore, the current standard antimicrobial susceptibility testing methods that predict therapeutic success with systemic agents are not so predictive for inhalation therapy [13]. The European Committee on Antimicrobial Susceptibility Testing (EUCAST), who define clinical break points in Europe, exclude break points for inhaled antibiotics [16] and, in the US, the Clinical and Laboratory Standards Institute (CLSI) has only defined breakpoints for inhaled amikacin in the treatment of MAC infections [13]. 

In summary, whilst inhaled antimicrobial therapy has distinct advantages for the treatment of lung infections, the development of new inhalation drug products for new indications has several challenges. Despite this, development pathways do exist and scientific advice from regulators sought during the development process can greatly improve the likelihood of a successful approval of a new inhaled agent. 

tranScrip has a team of pharmaceutical physicians and scientists who have a wealth of experience in developing antimicrobial agents, including those for inhalational use, and in interacting with regulatory agencies across the world to obtain scientific advice at each stage of a product’s development. If this is something that you believe may be beneficial in your drug development programme, please contact info@transcrip-partners.com.

1.    Himstedt, A., et al., Understanding the suitability of established antibiotics for oral inhalation from a pharmacokinetic perspective: an integrated model-based investigation based on rifampicin, ciprofloxacin and tigecycline in vivo data. J Antimicrob Chemother, 2022.
2.    Quon, B.S., C.H. Goss, and B.W. Ramsey, Inhaled antibiotics for lower airway infections. Ann Am Thorac Soc, 2014. 11(3): p. 425-34.
3.    Nichols, D.P., et al., Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities. Ann Am Thorac Soc, 2019. 16(5): p. 534-539.
4.    Arikayce SmPC. https://www.ema.europa.eu/en/documents/product-information/arikayce-liposomal-product-information_en.pdf (Accessed 28 October 2022).
5.    Arikayce USPI. https://www.arikayce.com/pdf/full_prescribing_information.pdf (Accessed 28 October 2022).
6.    Daniels, L.M., et al., Inhaled Antibiotics for Hospital-Acquired and Ventilator-Associated Pneumonia. Clin Infect Dis, 2017. 64(3): p. 386-387.
7.    Hou, S., Wu, J., Li, X., Shu, H. , Practical, regulatory and clinical considerations for development of inhalation drug products. Asian J Pharm Sci, 2015. 10: p. 490-500.
8.    EMA. Guideline on the requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of the therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003508.pdf, 2009.
9.    FDA Guidance for Industry. Metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products, chemistry, manufacturing, and controls documentation. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070573.pdf. 1998
10.    FDA Guidance for Industry. Nasal spray and inhalation solution, suspension, and spray drug products, chemistry, manufacturing, and controls documentation. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070575.pdf, 2002.
11.    EMA. Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf, 2018.
12.    Avila, A.M., et al., An FDA/CDER perspective on nonclinical testing strategies: Classical toxicology approaches and new approach methodologies (NAMs). Regul Toxicol Pharmacol, 2020. 114: p. 104662.
13.    Ekkelenkamp, M.B., et al., Establishing Antimicrobial Susceptibility Testing Methods and Clinical Breakpoints for Inhaled Antibiotic Therapy. Open Forum Infect Dis, 2022. 9(4): p. ofac082.
14.    Niederman, M.S., et al., Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial. Lancet Infect Dis, 2020. 20(3): p. 330-340.
15.    FDA Guidance for Industry. Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment., 2020.
16.    European  Committee  on  Antimicrobial  Susceptibility  Testing. Antimicrobial susceptibility tests on groups of organisms or agents for which there are no EUCAST breakpoints. . https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/General_documents/Organisms_and_agents_without_breakpoints_20160626.pdf., 2016.