Drugs (2014) 74:377–387

DOI 10.1007/s40265-014-0181-0

ADIS DRUG EVALUATION

Colistimethate Sodium Dry Powder for Inhalation: A Review

of Its Use in the Treatment of Chronic Pseudomonas aeruginosa
Infection in Patients with Cystic Fibrosis
Daniel Conole • Gillian M. Keating

Published online: 8 February 2014

Ó Springer International Publishing Switzerland 2014

Abstract Historically, the polymyxin antibacterial colistin
has been administered as intravenous or nebulized colisti-
methate sodium in patients with cystic fibrosis (CF) and
chronic Pseudomonas aeruginosa infection. More recently,
colistimethate sodium has been formulated as a dry powder
(ColobreatheÒ) to be administered via a hand-held Turbo-
spinÒ inhaler. Compared with nebulized colistimethate
sodium, the colistimethate sodium dry powder for inhalation
(DPI) formulation reduces treatment time and improves
patient convenience. Colistimethate sodium DPI is approved
in the EU for the treatment of chronic P. aeruginosa
infections in patients with CF aged C6 years. In a phase III
clinical trial in this patient population, it was determined that
the change in percent predicted forced expiratory volume in
1 s with colistimethate sodium DPI 1.6625 MIU (125 mg)
twice daily was noninferior to that with nebulized tobra-
mycin 300 mg/5 mL twice daily. Moreover, patients found
colistimethate sodium DPI easier to use than nebulized
tobramycin. Colistimethate sodium DPI was generally well
tolerated, with a similar adverse event profile to that of
nebulized tobramycin, except for a numerically higher
incidence of cough and abnormal taste. Most adverse events
The manuscript was reviewed by: S. Antoniu, Department of
Interdisciplinary Medicine-Nursing, University of Medicine and
Pharmacy, Iasi, Romania; W. Hengzhuang, Department of Clinical
Microbiology, Rigshospitalet, University Hospital of Copenhagen,
Copenhagen, Denmark; J. Li, Drug Delivery, Disposition and
Dynamics, Monash Institute of Pharmaceutical Sciences, Monash
University, Parkville, Victoria, Australia; Q. Zhou, Faculty of
Pharmacy, University of Sydney, Sydney, New South Wales,
Australia.
D. Conole
G. M. Keating (&)
Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
North Shore 0754, Auckland, New Zealand
e-mail: demail@springer.com
diminished after 28 days in patients receiving colistimethate
sodium DPI, with an occurrence similar to that in nebulized
tobramycin recipients. In conclusion, colistimethate sodium
DPI administered via the TurbospinÒ inhaler is a useful
option for the treatment of chronic P. aeruginosa infection
in patients with CF aged C6 years.
Colistimethate sodium dry powder for inhalation in
cystic fibrosis patients with chronic Pseudomonas
aeruginosa infection: a summary
Administered using a convenient, hand-held inhaler
(TurbospinÒ)
Achieves colistin concentrations in the sputum &20
times greater than the minimum inhibitory
concentration for P. aeruginosa
Noninferior to nebulized tobramycin in terms of the
improvement in lung function (percent predicted
forced expiratory volume in 1 s)
Generally well tolerated, with a similar profile to that
of nebulized tobramycin, but with a numerically
higher incidence of cough and abnormal taste
Was rated ‘very easy or easy to use’ and was
preferred by patients when compared with nebulized
tobramycin
1 Introduction
Cystic fibrosis (CF) is an autosomal recessive disease
triggered by mutations in the CF transmembrane
378
conductance regulator (CFTR) gene [1]. The hallmark of
the disease is abnormal chloride and sodium ion transport
across epithelial cell surfaces, leading to viscous secretions
in the lungs [2].
CF is one of the most common life-threatening autoso-
mal recessive disorder in the Western World [3], and has a
mean prevalence per 10,000 people of 0.737 in the EU [4].
Patients with CF are extremely prone to infection with
Pseudomonas aeruginosa, with chronic pulmonary infec-
tion occurring in more than 80 % of adult patients [5, 6]. In
patients with CF, P. aeruginosa infection accelerates the
progression of respiratory disease, resulting in lung tissue
destruction and loss of lung function [1]. One of the main
objectives of CF therapy is to prevent, limit and treat P.
aeruginosa infections to enhance survival and health-rela-
ted quality of life [1].
The introduction of antipseudomonal agents has greatly
enhanced the management of CF, resulting in reduced
pulmonary deterioration, fewer hospital admissions and
improved nutritional status [7, 8]. In particular, colistin, a
polymyxin antibacterial, has become a cornerstone for P.
aeruginosa infection treatment [9]. Historically, colistin
was administered intravenously to combat infections caused
by problematic Gram-negative bacteria; however, reports of
nephrotoxicity and neurotoxicity deterred its further use,
especially with the emergence of other antibacterials, such
as the aminoglycoside tobramycin, which was considered to
be less toxic [10–12]. More recently, a lack of treatment
options for multi-drug resistant bacteria such as Acineto-
bacter baumannii, P. aeruginosa and Klebsiella pneumo-
niae, has led to a resurgence of colistin as a treatment
option, particularly as an inhaled therapy [10].
Recent treatment guidelines recommend the use of
inhaled antibacterials against P. aeruginosa, such as nebu-
lized colistimethate sodium (a colistin prodrug) or tobra-
mycin [13]. This in fact has been the standard therapy for P.
aeruginosa infections since the 1980s [14]. Aerosolized
antibacterials are advantageous for delivering high drug
concentrations to the lung while minimizing systemic
exposure and toxicity [15, 16]. However, administration via
a nebulizer is complex and time consuming and is thought
to increase treatment burden and have a negative effect on
adherence [17–20]. Colistimethate sodium dry powder for
inhalation (ColobreatheÒ), referred to hereafter as colisti-
methate sodium DPI, is a dry-powder formulation of
micronized drug that is administered via a convenient hand-
held inhaler (TurbospinÒ). Colistimethate sodium DPI has
several advantages over nebulized colistimethate sodium,
including enhanced portability, a shorter administration
time and no requirement for device maintenance [14, 21].
This article discusses the drug delivery characteristics of
colistimethate sodium DPI administered via the Turbo-
spinÒ inhaler, and reviews its pharmacokinetics,
D. Conole, G. M. Keating
antipseudomonal efficacy and tolerability, with a particular
focus on how it compares with tobramycin nebulizer
solution for inhalation, in the treatment of chronic P.
aeruginosa infections in patients with CF aged C6 years.
2 Pharmacodynamic Properties
2.1 Mechanism of Antibacterial Activity
Colistimethate sodium is the inactive prodrug of colistin
(polymyxin E) [14, 22]. Colistin comprises a mixture of
several closely related cyclic polypeptides that are isolated
from Paenibacillus polymyxa var. colistinus; its two major
components are colistin A (polymyxin E1) and colistin B
(polymyxin E2) [12, 22]. To reduce toxicity, the drug is for-
mulated as colistin methanesulfonate sodium, referred to as
colistimethate sodium, which consists of sodium sulfomethyl
moieties attached to colistin’s amino groups (Fig. 1) [14, 22].
Colistin belongs to the polymyxin class of antibacterials,
which alter the structure and function of the outer and cyto-
plasmic membranes of bacteria, leading to damage of the
osmotic barrier, and fatal leakage of intracellular contents
[23]. Polymyxins are selective for Gram-negative bacteria
that have a hydrophobic outer membrane, as the mechanism
of action involves interaction with the lipid A component of
membrane lipopolysaccharide [12, 24].
2.2 Antibacterial Activity
Studies examining the antibacterial activity of colisti-
methate sodium are complicated by its in vivo conversion
to colistin [22, 25]. Therefore this section will focus on
colistin, the active form of the drug.
Colistin exhibits antibacterial activity against P. aeru-
ginosa, but also inhibits the growth of other Gram-negative
bacteria, including A. baumannii, Citrobactor spp., Esch-
erichia coli, Haemophilus influenza and K. pneumoniae
[14, 26, 27]. Colistin demonstrated potent in vitro activity
against clinical isolates of P. aeruginosa with a minimum
concentration required for 90 % growth inhibition (MIC90)
of 1 mg/L and a susceptibility rate of 99.6 % [27]. P.
aeruginosa isolates (n = 9,130) for this study were col-
lected from multiple centres worldwide from 2006 to 2009
[27]. It should be noted that the susceptibility breakpoint
(4 mg/L) established for the parenteral administration of
colistin may not be applicable to the inhaled route of
administration [28].
In in vitro static time-kill kinetic studies, colistin dem-
onstrated rapid concentration-dependent bactericidal
activity against P. aeruginosa [26, 29]. Similar concen-
tration-dependent activity was observed for colistin in
in vivo murine P. aeruginosa lung infection models [30].
Colistimethate Sodium Dry Powder for Inhalation: A Review
Fig. 1 Chemical structure of
colistimethate sodium
Both in vitro and in vivo studies suggested that time-
averaged exposure, or the free area under the concentra-
tion-time curve (fAUC):MIC ratio, is the parameter most
predictive of the antibacterial activity of colistin against P.
aeruginosa [25, 26, 31, 32]. Perhaps more pertinent to the
mucosal site of infection in the case of the target popula-
tion (pulmonary-impaired CF patients), it has been deter-
mined that the most predictive index for antibacterial
activity of colistin against P. aeruginosa biofilms in the
lung is the AUC to minimal biofilm inhibitory concentra-
tion (AUC:MBIC) ratio [33, 34].
2.3 Mechanisms of Resistance
P. aeruginosa demonstrates a marked ability to develop
resistance to antipseudomonal agents [35]. In vitro, popu-
lation analysis profiles revealed that a small proportion of
colistin-resistant cells exist in many clinical P. aeruginosa
isolates [26]. Colistin-resistant bacteria possess modified
lipopolysaccharide phosphate groups, which are substituted
with ethanolamine or aminoarabinose moieties [14, 36]. It
has been reported that dosing intervals may be important in
controlling the emergence of colistin resistance [26].
Generally, low rates of P. aeruginosa resistance to colistin
have been reported [27]. For example, among clinical
isolates of P. aeruginosa collected from the Asia-Pacific
region between 2006 and 2009 (n = 2,901), the resistance
rate against colisin was 0.4 % [27]. However, recent
studies also demonstrated that resistance to colistin emer-
ges more frequently in P. aeruginosa from patients with CF
in whom inhaled formulations have been used long term
379
[23, 37, 38]. Given their pharmacodynamic and structural
similarities, cross resistance between colistin and poly-
myxin B is anticipated [12]. However, because of the
distinctive mechanism of action of colistin, cross-resistance
to other drug classes would not be expected [14].
2.4 Other Effects
The effect of colistin on renal function is not well under-
stood [14]. Administration of intravenous colistimethate
sodium did not significantly affect renal function in
patients with CF [39–41] or serious infections [42, 43] in
some studies. However, nephrotoxicity was reported in
some recipients of intravenous colistimethate sodium in
other studies [44, 45]. Clinical manifestations of colistin-
induced nephrotoxicity include albuminuria, the presence
of urinary casts, reduced urine output and increased blood
urea nitrogen and creatinine levels [46]. The risk of
nephrotoxicity appeared to increase as the total cumulative
dose of colistimethate sodium increased [44, 45]. Neph-
rotoxicity appeared to be reversible upon discontinuation
of colistimethate sodium, although complete recovery may
take at least several weeks [10, 46].
Colistin also has the potential to cause neurotoxicity [47].
Colistin exhibits an effect on nerve conduction, resulting in
paraesthesias, visual alterations, neuromuscular blockade,
weakness and paralysis [10, 48, 49]. The drug’s effect is
postulated to be related to inhibition of acetylcholine release
at somatic nerve endings in skeletal muscle [14]. Colistin
may also affect sensory nerves and trigger vertigo and ataxia
by a mechanism that is not well understood [14]. As in the
380
case of nephrotoxicity, neurotoxicity can be controlled
through dose-reduction, although in more severe cases,
discontinuation may be necessary [46]. Neurotoxicity, which
usually occurs with prolonged colistin therapy, is usually
reversible following discontinuation [10].
The EU summary of product characteristics (SPC) states
that colistimethate sodium DPI should not be administered
in patients receiving parenteral or nebulized colistimethate
sodium, given that the effect of coadministration on plasma
concentrations is unpredictable and there may be an
increased risk of nephrotoxicity or neurotoxicity [50].
Coadministration of colistimethate sodium DPI with
potentially nephrotoxic or neurotoxic agents, including
nondepolarizing muscle relaxants, should be avoided [50].
Bronchoconstriction has been reported in patients with
CF receiving inhaled antibacterials, including nebulized
colistin [14, 51, 52]. However, results of lung function
studies in healthy volunteers and patients with CF found
that colistimethate sodium DPI 1.6625 MIU (equivalent to
125 mg) did not induce bronchoconstriction [14]. If bron-
chospasm and coughing occur on inhalation, the EU SPC
states that they may be ameliorated by administration of
b2-agonists, either prior to or following administration of
colistimethate sodium DPI [50].
3 Device Characteristics and Drug Delivery
The TurbospinÒ powder inhaler device uses the patient’s
inspiratory flow to activate the delivery of colistimethate
sodium dry powder into the lungs. The device is hand-held,
contains no excipients, is reusable and takes less than 60 s
to administer the drug [2, 53]. The patient has to insert a
1.6625 MIU colistimethate sodium capsule (equivalent to
125 mg) into the chamber of the TurbospinÒ inhaler (with
the larger part downwards), push the piston fully in to
pierce the capsule (allowing the capsule contents to be
inhaled), and then close their mouth over the mouthpiece
[50, 54]. Post-inhalation, the patient should hold their
breath for 10 s or for as long as is comfortable before
breathing out to maximize lung deposition. Patients are to
repeat this process until the capsule is empty [50].
In a study in ten patients with CF, approximately 12 %
of the dose was deposited in the whole lung following
administration of 1.6625 MIU of colistimethate sodium
DPI using the TurbospinÒ device, with or without salbu-
tamol (albuterol) pretreatment; this compared with 6 %
whole lung deposition for patients receiving nebulized
colistimethate sodium 1 MIU [14]. The extent of drug
deposition in the oropharynx was 2.9 % for the nebulized
formulation of colistimethate sodium versus approximately
70 % for colistimethate sodium DPI, with or without sal-
butamol pretreatment [14].
D. Conole, G. M. Keating
Thus, one capsule of colistimethate sodium DPI
1.6625 MIU twice daily and nebulized colistimethate
sodium 2 MIU twice daily should result in similar lung
deposition in patients with CF [55], and a regimen of
colistimethate sodium DPI 1.6625 MIU twice daily was
adopted for phase II and III clinical trials [14].
4 Pharmacokinetic Properties
This section summarizes the pharmacokinetic properties of
the recommended dosage of colistimethate sodium DPI (one
capsule of 1.6625 MIU inhaled twice daily) reported in the
FREEDOM study (see also Sect. 5) that used the approved
TurbospinÒ inhaler [21]. Supplementary pharmacokinetic
data were obtained from a phase I single-dose study in
patients with CF and P. aeruginosa lung infection receiving
nebulized colistimethate sodium 2 MIU (158 mg) [56].
4.1 Absorption and Distribution
Because of difficulties associated with obtaining samples
from the lower airways, limited data are available on the
absorption of colistimethate sodium into the circulation from
the lower respiratory tract [57]. Although the extent of
absorption and distribution of colistimethate sodium DPI
into clinically relevant body compartments (e.g. serum,
sputum, urine) is not well characterized, it may be at least as
extensive as that observed with nebulization [50]. Variable
absorption was reported with administration of nebulized
colistimate sodium, with serum concentrations ranging from
undetectable to C4 mg/L [50]. With nebulized colistimate
sodium, the extent of absorption may depend on aerosol
particle size, the nebulizer system and lung status [50].
In a multicentre study examining the pharmacokinetics
of colistin following administration of nebulized colisti-
methate sodium in patients with CF, the serum concen-
tration of colistin A (the quantitative marker for colistin
used in this study) was lower than would be seen with
systemic administration [56]. Following administration of
nebulized colistimethate sodium, a mean 4.3 % of the
inhaled dose was recovered in the urine [56]. Concentra-
tions of colistin A in the sputum reached a maximum of
&40 mg/L (value estimated from graph) 1 h after inhala-
tion [56], equating to approximately ten times the suscep-
tibility breakpoint for P. aeruginosa of 4 mg/L stipulated
by the British Society for Antimicrobial Chemotherapy
[28]. In addition, sputum concentrations of colistin A
remained greater than the 4 mg/L susceptibility breakpoint
even 12 h post-administration [56]. It is important to note
that only measuring colistin A will underestimate total
colistin exposure, given that colistin B is also an important
component of the active drug.
Colistimethate Sodium Dry Powder for Inhalation: A Review
These results appear to be in agreement with those of the
more recent FREEDOM study, which examined the use of
colistimethate sodium DPI administered using the Turbo-
spinÒ inhaler [21]. Of 484 patient serum samples, all but
one were just detectable or below the limit of detection for
colistin (2 mg/L). Most of the urine samples (78 %)
showed concentrations of colistin of \8 mg/L, whereas in
the sputum, 38 % of samples were observed to have
colistin concentrations of [128 mg/L, a value that is 32
times greater than the susceptibility breakpoint of colistin
[21]. Overall, sputum concentrations of colistin were &20
times greater than the MIC for colistin [21].
Colistimethate sodium is not absorbed from the gastro-
intestinal tract to an appreciable extent in healthy indi-
viduals [50].
Unbound fractions of colistin ranged from 26 to 41 %,
with no obvious differences in plasma protein binding
observed between critically ill patients and healthy vol-
unteers [58]. In 12 adult patients with CF and P. aeru-
ginosa lung infection who received intravenous
colistimethate sodium, the mean volume of distribution at
steady-state (Vdss) was 340 mL/kg [59]. However, the Vdss
of intravenous colistimethate sodium in another study was
90 mL/kg [60]. It is important to note, however, that these
data were obtained using intravenous administration, and
so may not be clinically relevant for the colistimethate
sodium DPI formulation [61].
4.2 Metabolism and Elimination
In patients administered the drug intravenously, colisti-
methate sodium is hydrolysed to colistin and various
sulfomethylated derivatives [10, 11, 57]. Colistimethate
sodium is mainly eliminated renally, whereas colistin
undergoes extensive renal tubular reabsorption and is
mainly eliminated by nonrenal routes [10, 11]. Following
parenteral administration of colistimethate sodium to sub-
jects with normal renal function, &40 % and &80 % of
the dose was recovered in urine within 8 and 24 h,
respectively [14]. In rats receiving intravenous colisti-
methate sodium, &60 % of the dose was recovered in the
urine within 24 h, with &33 % present as colistin [62]. No
biliary excretion was observed in humans; however, pul-
monary clearance via sputum has been proposed to con-
tribute to overall clearance following administration of
nebulized colistimethate sodium [14].
The elimination of colistimethate sodium following
inhalation has not been extensively studied; however, a
study in patients with CF failed to detect any colistimethate
sodium in the urine after 1 MIU was inhaled twice daily via
a nebulizer for 3 months [14]. It has been stated that the
elimination characteristics of colistin following adminis-
tration of nebulized colistimethate sodium did not differ
381
significantly from those previously reported for systemic
administration [56, 59, 60].
No drug-drug interaction or special patient population
studies have been conducted for colistimethate sodium DPI
[14]. In vitro, colistin and colistimethate sodium did not
induce the activity of the cytochrome P450 (CYP) enzymes
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or
CYP3A4/5 [50].
5 Therapeutic Efficacy
The antipseudomonal efficacy of colistimethate sodium
DPI in patients with CF and chronic P. aeruginosa lung
infection aged C6 years was evaluated in the randomized,
open-label, multicentre, phase III FREEDOM study [21].
The trial was designed to evaluate whether colistimethate
sodium DPI was noninferior to tobramycin nebulizer
solution for inhalation. In this study, patients were ran-
domized to receive either continuous treatment over
24 weeks with colistimethate sodium DPI (one capsule of
1.6625 MIU twice daily), or three 28-day courses of neb-
ulized tobramycin (300 mg/5 mL twice daily). Each course
of nebulized tobramycin was followed by a 28-day off
period. All patients received at least two courses of nebu-
lized tobramycin prior to randomization [21].
Table 1 summarizes patient baseline characteristics and
trial design details [21]. The primary endpoint was the
change in mean percent predicted forced expiratory vol-
umes in 1 s (FEV1) from baseline to week 24. Other key
efficacy measures included susceptibility of respiratory
tract P. aeruginosa isolates, changes in forced vital
capacity (FVC) and forced expiratory flow between 25 and
75 % of vital capacity (FEF25–75), and device ease of use
[21].
The randomized trial included patients with FEV1 of
25–75 % predicted [21]. Chronic P. aeruginosa lung
infection and a stable clinical condition were further
requirements for patient inclusion. Exclusion criteria are
summarized in Table 1.
5.1 Lung Function
Changes in percent predicted FEV1 demonstrated that
colistimethate sodium DPI was noninferior to nebulized
tobramycin for the treatment of chronic P. aeruginosa
infection in patients with CF [21]. The adjusted mean
difference between colistimethate sodium DPI and nebu-
lized tobramycin for the change from baseline in percent
predicted FEV1 in the intent-to-treat (ITT) population after
24 weeks was -0.97 % (95 % CI -2.74 to 0.86), and the
lower limit was above the predefined noninferiority margin
of -3 % (Table 2) [21]. Results for the ITT-completer, per
382 D. Conole, G. M. Keating

Table 1 Baseline patient characteristics (intent-to-treat population) the treatment of chronic Pseudomonas aeruginosa infection in
and trial design details of a randomized, open-label, multicentre, patients with cystic fibrosis [21]
phase III study of colisitmethate sodium dry powder for inhalation in
CDPI (n = 183) TIS (n = 191)

Baseline characteristics
Mean age (years) [range] 21.3 [6–55] 20.9 [6–56]
Male/female (%) 56.3/43.7 52.9/47.1
Mean bodyweight (kg) 49.4 48.7
Mean BMI (kg/m2) 18.7 18.5
Percentage of patients with percent predicted FEV1 \50 % 44.8 49.7
Mean time since diagnosis (years) 17.1 17.5
Inclusion criteria Patients with CF aged C6 years; FEV1 of 25–75 % predicted; chronic
Pseudomonas aeruginosa lung infectiona; stable clinical conditionb
Exclusion criteria Presence of Burkholderia cepacia complex infection in the airways; on-going
pulmonary exacerbation (based on a modified Fuchs definition); sensitivity to
any study medication
Primary endpoint Change in mean percent predicted FEV1 from baseline at week 24c
Key secondary endpoints Susceptibility of respiratory tract P. aeruginosa isolates from both groups to
colistin and tobramycind; change in FVC, FEF25–75; device ‘ease of use’

BMI body mass index, CDPI colistimethate sodium dry powder for inhalation, CF cystic fibrosis, FEF25–75 forced expiratory flow between 25
and 75 % of the vital capacity, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, TIS tobramycin nebulizer solution for inhalation
a
Chronic P. aeruginosa lung infection was defined as C50 % of sputum samples (minimum of three) being positive for P. aeruginosa over the
12 months prior to the first day of trial medication, or for two positive samples over the 6 months prior to the first day of trial medication
b
Stable clinical condition was defined as no evidence of a current acute respiratory exacerbation at the pre-run visit, and in the investigator’s
opinion, no likelihood of an acute respiratory exacerbation at the start of treatment
c
The Knudson correction was used for all pulmonary function assessments
d
The breakpoints used to determine susceptibility were based on British Society for Antimicrobial Chemotherapy recommendations (2001) [28].
Colistin breakpoints were B4 mg/L for susceptibility and [4 mg/L for resistance, and tobramycin breakpoints were B2 mg/L for susceptibility
and C8 mg/L for resistance

protocol (PP) and PP-completer analyses are also shown in
Table 2.
In both the ITT (0.01 L; 95 % CI -0.09 to 0.10) and PP
(-0.02 L; 95 % CI -0.12 to 0.08) populations, the
adjusted treatment differences for the FVC change from
baseline to week 24 were not statistically significant [21].
Similarly, no significant adjusted treatment difference was
seen for the change from baseline in FEF25–75 in the PP
population (-0.12 L/s; 95 % CI -0.26 to 0.01). However,
the change from baseline in FEF25–75 (adjusted treatment
difference -0.12 L/s; 95 % CI -0.23 to -0.01;
p = 0.038) for the ITT population at study end indicated
that nebulized tobramycin was significantly favoured over
colistimethate sodium for this lung function parameter
(Table 2) [21].
5.2 Microbiology
No changes in the susceptibility of P. aeruginosa isolates to
colistin were observed in either the colistmethate sodium
DPI or nebulized tobramycin treatment groups [21]. The
minimum concentration required for 50 % growth inhibition
(MIC50) of P. aeruginosa for colistin remained steady
throughout the 24-week study period at &0.38 mg/L in both
treatment groups. The MIC90 values for colistin ranged from
0.5 to 1.0 mg/L over the same period. At no stage during the
study was the 4 mg/L resistance breakpoint exceeded. For
tobramycin, the MIC50 and MIC90 values ranged from 1 to
1.5 mg/L and from 8 to 96 mg/L, respectively [21].
5.3 Other Outcomes
Colistimethate sodium DPI administered via the Turbo-
spinÒ inhaler was rated by patients as easier to use than the
nebulized tobramycin [21]. In the ITT population, 51.9 %
of users of the colistimethate sodium DPI TurbospinÒ
device rated it ‘very easy to use’, compared with only
9.9 % of patients in the nebulized tobramycin group.
Moreover, 90.7 % of users rated the colistimethate sodium
DPI TurbospinÒ device either ‘very easy or easy to use’,
whereas only 53.9 % of patients in the nebulized tobra-
mycin group gave this rating (p \ 0.001) [21].
Of the patients randomized to colistimethate sodium
DPI, 65.6 % preferred this treatment over nebulized
tobramycin, which they had received prerandomization
[21]. The majority (80.6 %) of children aged 6–12 years
Table 2 Effect of colistimethate sodium dry powder for inhalation vs. tobramycin nebulizer solution for inhalation on lung function in patients aged C6 years with cystic fibrosis and chronic
Pseudomonas aeruginosa infection. Results of the FREEDOM trial [21]
Treatmenta (no. of pts) Percent predicted FEV1 FVC (L) FEF25–75 (L/s)
Mean change from Logarithmically Adjusted treatment Week 24 Adjusted treatment Week 24 Adjusted treatment
baseline (baseline)b transformed datac difference (95 % CI)d (baseline) difference (95 % CI) (baseline) difference (95 % CI)

ITT analysis
CDPI (183) -0.90 (49.14) 0.964 -0.97 (-2.74 to 0.86) 2.51 (2.52) 0.01 (-0.09 to 0.10) 1.14 (1.23) -0.12 (-0.23 to -0.01)*
TIS (190) 0.35 (50.80) 0.986 2.51 (2.49) 1.20 (1.12)
ITT-completer analysis
CDPI (153) 0.39 0.988 -0.29 (-2.21 to 1.71)
Colistimethate Sodium Dry Powder for Inhalation: A Review

TIS (171) 0.78 0.993

PP analysis
CDPI (141) -0.30 0.974 -1.10 (-3.07 to 0.96) 2.46 (2.46) -0.02 (-0.12 to 0.08) 1.12 (1.20) -0.12 (-0.26 to 0.01)
TIS (157) 1.12 0.997 2.50 (2.46) 1.16 (1.08)
PP-completer analysis
CDPI (120) 0.83 0.997 -0.56 (-2.70 to 1.70)
TIS (141) 1.60 1.005
CDPI colistimethate sodium dry powder for inhalation, FEF25–75 forced expiratory flow between 25 and 75 % of the vital capacity, FEV1 forced expiratory volume in 1 s, FVC forced vital
capacity, ITT intent-to-treat, PP per protocol, TIS tobramycin nebulizer solution for inhalation
* p = 0.038
a
CPDI 1.6625 MIU twice daily was administered for 24 weeks, and three 28-day courses of TIS 300 mg/5 mL twice daily were administered, with each course of TIS followed by a 28-day off
period
b
Data obtained from the EU assessment report [14]
c
Results did not follow a normal distribution and were therefore evaluated using log-transformation analysis
d
Adjusted treatment difference (CDPI - TIS) obtained using formula (M 9 (ratio - 1)), where M is the unadjusted TIS geometric mean. Noninferiority was shown if the lower limit of the
95 % CI was above the predefined noninferiority margin of -3 %
383
384 D. Conole, G. M. Keating

80 (62.6 %) and throat irritation (45.5 %) in the colistimethate

70 CDPI 1.6625 MIU (125 mg) twice daily (n = 187) sodium DPI group compared with the nebulized tobramycin
TIS 300 mg/5 mL twice daily (n = 193) group (27.5 and 28.0 %, respectively) [21]. By system organ
Incidence (% of patients)

60 class, the most commonly occurring adverse events in

50 colistimethate sodium DPI recipients were respiratory, tho-
racic and mediastinal disorders (Fig. 2) [data obtained from
40
the EU assessment report] [14]. Most adverse events
30 diminished after 28 days in patients receiving colistimethate
sodium DPI, with an occurrence similar to that in nebulized
20
tobramycin recipients [21]. It should be noted that both
10 treatment groups received at least two courses of nebulized
0
tobramycin prior to randomization, meaning that patients
who did not tolerate nebulized tobramycin may have with-
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si
tio

oe

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in

fo

on
LR
ou

ty
ez

om
ita

pn

co

ph

op
drawn from the study in the pre-randomization phase [21].
C

he
irr

ys

sc
e

ys

m
W
tiv
D
at

di

ae
D
uc

Two deaths occurred in the nebulized tobramycin group;

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H
Th

od

he
Pr

however, these were attributed to CF-related lower respi-

Fig. 2 Tolerability of colistimethate sodium DPI (CDPI) vs. tobra- ratory tract infection in both cases, and therefore these
mycin nebulizer solution for inhalation (TIS) in patients aged events were assumed to be unrelated to the study medica-
C6 years with cystic fibrosis and chronic Pseudomonas aeruginosa tion [21]. No clinically relevant changes in bodyweight,
infection in the FREEDOM study [21]. Only the most common
respiratory, thoracic and mediastinal adverse events (incidence of
body mass index or growth were observed in either treat-
[10 %) in the CDPI treatment group are displayed (obtained from ment group. No significant treatment-related changes in
the EU assessment report [14]). LRTI lower respiratory tract infection haematological, biochemical or urinalysis parameters were
observed [21].
also preferred colistimethate sodium DPI over nebulized
tobramycin [21].
7 Dosage and Administration

6 Tolerability Colistimethate sodium DPI is approved in the EU for the

management of chronic pulmonary infections associated
In the FREEDOM trial in patients with CF and chronic P. with P. aeruginosa in patients with CF aged C6 years [50].
aeruginosa lung infection, colistimethate sodium DPI was The EU label states that the safety and efficacy of colisti-
generally well tolerated, with most adverse events being of methate sodium DPI has not been established in patients
mild to moderate severity (95 %) and resolving without aged \6 years.
consequence [21]. It should be noted that sore throat or All patients within the approved age range, regardless of
mouth has also been reported with nebulized colistimethate bodyweight, should receive the recommended dosage of
sodium [50]. colistimethate sodium DPI, which is one 1.6625 MIU cap-
Adverse events (all causes) were reported by 93.6 and sule administered twice daily via the TurbospinÒ inhaler. It
89.1 % of patients receiving colistimethate sodium DPI is also recommended that each dose be separated by as close
and nebulized tobramycin, respectively [21]. The inci- to 12 h as possible. For patients receiving other inhaled
dences of treatment-related adverse events and discontin- medications or chest physiotherapy, it is advised that colis-
uations because of adverse events were numerically higher timethate sodium DPI be administered subsequently.
for colistimethate sodium DPI (82.3 and 9.7 %, respec- Treatment can be continued for as long as the physician
tively) than for nebulized tobramycin (46.6 and 1.6 %, considers that the patient is obtaining clinical benefit [50].
respectively). A total of 71.7 % of adverse events in the Local prescribing information should be consulted for
colistimethate sodium DPI group were thought to be contraindications, special warnings and precautions per-
‘definitely related’ to the drug, versus 26.4 % in the neb- taining to colistimethate sodium DPI.
ulized tobramycin group [14]. Serious adverse events
occurred in 4.3 and 6.2 % of colistimethate sodium DPI
and nebulized tobramycin recipients, respectively [21]. 8 Colistimethate Sodium Dry Powder for Inhalation:
Cough was the most common adverse event, occurring in Current Status
75.4 % of colistimethate sodium DPI recipients versus
43.5 % of nebulized tobramycin recipients [21]. There was Colistimethate sodium DPI administered via the Turbo-
also a numerically higher incidence of abnormal taste spinÒ inhaler was noninferior to tobramycin nebulizer
Colistimethate Sodium Dry Powder for Inhalation: A Review
solution for inhalation for the treatment of chronic P.
aeruginosa lung infection in patient with CF aged
C6 years, as demonstrated by the change in percent pre-
dicted FEV1 at 24 weeks [21]. Maintenance of percent
predicted FEV1 is a predictor of improved survival in
patients with CF [63].
Colistimethate sodium DPI was generally well toler-
ated, with a similar profile to that of nebulized tobra-
mycin, with the exception of a numerically higher
incidence of cough and abnormal taste. However, these
adverse events are typical of inhaled dry powder ther-
apies, reflecting the large amount of drug deposited in
the oropharynx [64]. A numerically higher number of
withdrawals because of adverse events were observed in
the colistimethate sodium DPI group versus the nebu-
lized tobramycin group. This may be explained by the
fact that each treatment group received at least two
cycles of nebulized tobramycin prior to randomization,
meaning that patients who did not tolerate nebulized
tobramycin may have withdrawn prior to the start of the
trial, possibly resulting in a study design that selected
for patients who would tolerate nebulized tobramycin
[21].
Historically, the potential to generate resistance to
colistin has been reported to be low [59, 65–67]; however,
data on acquired resistance to colistin and related poly-
myxins are limited [68]. More recently, studies have
demonstrated that resistance to colistin emerges more fre-
quently in P. aeruginosa from patients with CF in whom
inhaled formulations have been used [23, 37, 38]. No
changes in susceptibility of P. aeruginosa isolates to
colistin were seen in patients receiving colistimethate
sodium DPI in the pivotal trial [21].
Compared with nebulized tobramycin, patients found
the colistimethate sodium DPI TurbospinÒ inhaler easier to
use, and although adherence and potential impact on long-
term efficacy were not assessed in this study, based on
previous studies [19, 20, 69], it is anticipated that the
improved convenience and reduced complexity of use of
the colistimethate sodium DPI TurbospinÒ inhaler will
have a positive impact on treatment adherence.
Colistimethate sodium DPI is approved in the EU for
the treatment of chronic pulmonary infections associ-
ated with P. aeruginosa in patients with CF aged
C6 years [50]. Because of data limitations and study
heterogeneity, an indirect comparison of colistimethate
sodium DPI with the recently EU approved tobramycin
inhalation powder (TOBIÒ) is not possible [70],
although a prospective study directly comparing these
two therapies would be of interest. In conclusion,
colistimethate sodium DPI administered via the Turbo-
spinÒ inhaler represents a useful option for the
385
treatment of chronic P. aeruginosa infection in patients
with CF aged C6 years.
Data selection sources: Relevant medical literature (including
published and unpublished data) on colistimethate sodium dry
powder inhaler was identified by searching databases including
MEDLINE (from 1946) and EMBASE (from 1996) [searches last
updated 20 January 2014], bibliographies from published litera-
ture, clinical trial registries/databases and websites. Additional
information was also requested from the company developing the
drug.
Search terms: colistimethate sodium, colistimethate, colomycin,
Colobreathe, cystic fibrosis.
Study selection: Studies in patients with cystic fibrosis with
Pseudomonas aeruginosa infection who received colistimethate
sodium dry powder inhaler. When available, large, well designed,
comparative trials with appropriate statistical methodology were
preferred. Relevant pharmacodynamic and pharmacokinetic data
are also included.
Disclosure The preparation of this review was not supported by any
external funding. During the peer review process, the manufacturer of
the agent under review was offered an opportunity to comment on this
article. Changes resulting from comments received were made by the
author on the basis of scientific and editorial merit.
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