Advanced Drug Delivery Reviews 85 (2015) e6e7

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Advanced Drug Delivery Reviews

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Commentary

Comment on: Inhaled antimicrobial therapyBarriers to effective

treatment, by J. Weers, Inhaled antimicrobial therapy Barriers to
effective treatment, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/
10.1016/j.addr.2014.08.013
David Cipolla , Juergen Froehlich, Igor Gonda
Aradigm Corporation, 3929 Point Eden Way, Hayward, CA 94545, USA

Weers captured well the background information and exciting landscape of inhaled antibiotics [1]. However, there are some inaccuracies
and signicant omissions that we wish to point out.
Firstly, it is essential to emphasize what we think should have been
included but is absent from Dr. Weers' review on inhaled antimicrobial
therapy: a successful therapy means dosage regimens that have the
right balance of safety and efcacy. It is therefore in our view incorrect
to separate the two: all antibiotics by denition kill bacteria but if they
can only do it with dosage regimens in which the harm exceeds the benet, they are therapeutic failures. Therefore, we believe it is incorrect to
compare inhaled antibiotics by analyzing their antimicrobial efcacy
and adverse effects separately. Ideally, it should be done in terms of
some composite outcomes meaningful for the patients, such as a reduction in the frequency of pulmonary exacerbations and an improvement
in the quality of life. Even in the absence of such composite scores, it
would be at least valuable to provide comparable objective efcacy
measures together with the adverse effects from clinical trials in similar
populations. For example, while the mechanistic explanation of the
frequency of cough in Fig. 6 is very valuable, it would have been
even more valuable to provide the reader with data on the antipseudomonal activity and lung function changes in cystic brosis,
non-cystic brosis bronchiectasis and COPD patients together with the
frequency of cough and bronchoconstriction.
In section 3.2 the author has an opportunity to make an apples to
apples comparison of tolerability of dry powder inhalers (DPIs) to nebulized solutions. In the analysis of the Tobi Podhaler vs. Tobi delivered
via jet nebulizer similar potency was achieved in the same population
of patients but the respiratory adverse event prole was different for
the powder with an increase in incidence of cough (48.4% vs. 31.1%)
and a higher rate of discontinuation of therapy (14.0% vs. 8.1%). We
nd it surprising that the author then generalizes in the same section

This comment is part of the Advanced Drug Delivery Reviews theme issue on Inhaled
antimicrobial chemotherapy for respiratory tract infections: Successes, challenges and the
road ahead.
DOI of original article: http://dx.doi.org/10.1016/j.addr.2014.08.013.
Corresponding author.
E-mail address: cipollad@aradigm.com (D. Cipolla).

http://dx.doi.org/10.1016/j.addr.2015.04.015
0169-409X/ 2015 Elsevier B.V. All rights reserved.

that Indeed, it is clear that cough with the dry powders was comparable to the nebulized liquids in the 28-day placebo-controlled trials
which clearly contradicts the data from the most appropriate and direct
evaluation of dry powder vs. liquid aerosols in this article.
Tables 1 and 2 are incomplete. We would like to point out that
Aradigm has been developing two inhaled liposomal ciprooxacin
products (licensed to Grifols): Lipoquin liposomally encapsulated
ciprooxacin, and Pulmaquin which combines a mixture of free and
encapsulated ciprooxacin [2,3]. Lipoquin has been tested in a Phase
2a study in cystic brosis patients [4] and is also being tested (along
with Pulmaquin) for non-tuberculous mycobacteria infections [5] and
against bioterrorism infections such as plague, tularemia and Q-fever
[6,7]. Unfortunately, the results from the cystic brosis trial with
Lipoquin are missing from Fig. 3: Lipoquin showed a 6.9% mean increase
in FEV1 against baseline in 22 adult CF patients (mean age of 28.9) after
two weeks of dosing [4]. This response is differentiated from the DPI formulations which show no improvement in FEV1 in adult CF patients
(see modied Fig. 3 below).

D. Cipolla et al. / Advanced Drug Delivery Reviews 85 (2015) e6e7

Table 4 has a sub-title Critical errors for inhaled antibiotic delivery

systems, yet it does not appear to focus on critical errors but rather
product attributes. Many of the attributes, such as once daily dosing
with liposomal formulations, or the need to reconstitute and store at refrigerated conditions, are product dependent, not inhaler-dependent.
Most of these attributes would have been better placed in the table describing individual products, rather than making generalizations about
inhaler categories. As an example of providing confusing information
for the reader, a statement is made in the DPI section that says Dry
powders enable the largest decrease in treatment burden: shortest administration time, no cleaning requirements, and improved portability.
This generalization about improved convenience of DPIs appears to contradict the Instructions for Use for the Tobi Podhaler [8]: there are a total
of 23 steps, and one of those steps says to repeat 12 steps for each of
three additional capsules. This translates into a total of 59 steps for
each dose interval, or 108 steps every day. Further, for patients who
are unable to inhale the full content of each capsule in a single breath,
the instructions suggest that the patients should inhale from the same
capsule again until the capsule is empty.
We do not agree with the authors statement that Achieving a consensus on the denition of an infective exacerbation is critical as new
treatments move forward into late stage development. Firstly, not
every therapeutic intervention with inhaled antibiotics needs to dene
prospectively the same endpoint pulmonary exacerbations are just
one example of a meaningful endpoint. For example, the objective endpoint in the treatment of tuberculosis or non-tuberculosis mycobacterial infections in the lung may be sputum culture conversion rather than
pulmonary exacerbations. Quality of life based on patient reported outcomes has been also used as the primary endpoint in late stage trials
(e.g., Phase 3 studies with Cayston in cystic brosis and non-cystic brosis bronchiectasis). If the primary endpoint is about infective pulmonary
exacerbations (i.e. frequency of exacerbations or time to rst exacerbation), then it is important to ascertain that the investigators use a consistent approach to detecting the onset and resolution of a pulmonary
exacerbation as prospectively dened for that clinical trial. The
resulting clinical outcome is then captured in the information for the
prescribers and patients when the treatment gets approved. The product label is not meant to and in practice is unlikely to be the same
for every treatment, and therefore it is not necessary to have the same
denition of pulmonary exacerbation for each new approved treatment.
For example, one treatment may be benecial for the patients because it
reduces the frequency of pulmonary exacerbations as its primary
impact, whereas another treatment may succeed in the primary endpoint an improvement in one or more domains of quality of life of
the patients. Moreover, although there is a variety of denitions of
pulmonary exacerbations for cystic brosis and non-cystic brosis
bronchiectasis, most of these are actually very similar and include typically symptomatic detection based on the presence of dyspnea, wheezing, fever, fatigue, and changes in lung function, radiographic images,
sputum and cough. Most of the differences in denitions are about the
grouping of the symptoms and the nature and quantity of the symptoms
to be present concurrently for the event to be a pulmonary exacerbation. In contrast, one of the key challenges facing development of
new inhaled antibiotics not mentioned by the author is the regulatory
requirement to conduct pivotal well-controlled studies for marketing
authorization, including the use of placebo. The situation is particularly
challenging to enroll patients who may be already treated successfully
with another inhaled antibiotic in which case their willingness to

e7

participate in a placebo-controlled trial is often low. On top of it, the

EU regulators request active comparator for a new inhaled antibiotic
for cystic brosis, and therefore two different Phase 3 clinical programs
are likely required if approval is sought both in EU and US.
As Weers says, the optimization of the pharmacokinetics of inhaled
antibiotics may lead to better treatments and has actually already
been accomplished: one example of such an effort is the development
of Pulmaquin which combines immediately available ciprooxacin
with liposomally encapsulated ciprooxacin (Lipoquin). In Phase 2
clinical trials, Pulmaquin appears to have superior anti-pseudomonal effect vs. Lipoquin and promising safety and tolerability, too, in patients
with non-cystic brosis bronchiectasis [9]. The development of novel
formulations is also driven by the need to nd more effective treatments
for intracellular infections such as non-tuberculous mycobacteria [5]
that are often present especially in the more severe cystic brosis and
non-cystic brosis bronchiectasis patients. Such microorganisms, in
addition to being present in the plankton and biolms, are harbored in
macrophages [10]. Liposomally encapsulated ciprooxacin has
been shown to have superior anti-NTM activity compared to the
unencapsulated drug, both against NTM in macrophages and in biolms
[5]. In addition, multiple targets need to be considered to address effective treatment options considering the complexity of the pathology of
the lung microbiome in these patients. For example, if both NTM and
Pseudomonas aeruginosa are present in a patient, then effective treatment against both types of organisms is needed, that is also active in
the plankton, biolm and macrophages.
We hope that these constructive comments will assist in balancing
the considerations for the development of much needed inhaled antimicrobial therapies in the management of serious pulmonary infections.
References
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