Adv Ther (2015) 32:1–9 DOI 10.1007/s12325-015-0179-3

REVIEW

Use of Inhaled Tobramycin in Cystic Fibrosis Michal Shteinberg • J. Stuart Elborn

To view enhanced content go to www.advancesintherapy.com Received: November 28, 2014 / Published online: January 27, 2015 Ó Springer Healthcare 2015

ABSTRACT

eradication of early acquisition of P. aeruginosa.

Chronic infection with Pseudomonas aeruginosa

Recently, a dry powder inhalation (DPI) form of tobramycin has become available, which is

is associated with poor outcomes in patients

more convenient for administration and has

with cystic fibrosis (CF). It leads to a reduced quality of life, acceleration of the decline in

comparable efficacy to the tobramycin solution. This DPI, the PodhalerTM (Novartis

lung function, and increased frequency and severity of pulmonary exacerbations.

Pharmaceuticals Corporation, East Hanover, NJ, USA), requires less time for treatment

Tobramycin, administered by inhalation as a

delivery and is more portable than a nebulizer,

long-term therapy, decreases bacterial density in airways, reduces exacerbation frequency, and

and so is a welcome additional therapeutic option for many patients.

improves quality of life and lung function in patients with chronic P. aeruginosa infection. In the last decade, tobramycin inhalation has become an important contributor to CF treatment as a means to control chronic

Keywords: Cystic inhalation;

fibrosis;

Pseudomonas

Dry

powder aeruginosa;

Tobramycin

infection and as a first-line treatment for the

INTRODUCTION Electronic supplementary material The online version of this article (doi:10.1007/s12325-015-0179-3) contains supplementary material, which is available to authorized users. M. Shteinberg (&) Pulmonology and CF Center, Carmel Medical Center, and the Rappaport Faculty of Medicine, Haifa, Israel e-mail: [email protected] M. Shteinberg
J. S. Elborn Center for Infection and Immunity, Queen’s University of Belfast, Belfast, UK

Cystic fibrosis (CF) is the most common lifeshortening genetic disorder and is caused by mutations in both alleles of the CF transmembrane conductance regulator (CFTR) gene [1]. This disorder results in reduced function of a chloride channel present in various organs, importantly, the lungs, pancreas, intestine, sweat glands, and reproductive tract, causing impairment of

Adv Ther (2015) 32:1–9

2

function in these organs. In the lungs, loss of

clinical trials that provide the evidence for its

CFTR function causes accumulation of thick

efficacy, and the recent development of the dry

secretions in the bronchi, causing chronic and progressive lung disease. Retained respiratory

powder formulation of inhaled tobramycin. This review is based on previously conducted

secretions cause bronchiectasis and lung infection. In the past decade, the average

studies, and does not involve any new studies of human or animal subjects performed by any of

survival of patients with CF has increased to

the authors.

nearly 40 years [2]. This improvement in survival is due to many factors, among which are improved treatments such as the development of antimicrobial agents directed

INFECTION WITH PSEUDOMONAS AERUGINOSA IN CF

to treat infections common to patients with CF.

Infection of the airways is a common finding in

A number of inhaled antibiotics are licensed for chronic therapy, but not all are universally

several airway diseases. Infection occurs universally in CF, but is also common with

available (Table 1) [3]. This review focuses on the development of inhaled tobramycin, the

other chronic conditions such as non-CF bronchiectasis

and

chronic

obstructive

Table 1 Available antibiotic preparations for inhalation in cystic fibrosis patients Characteristic

Inhaled antibiotic

Dose Volume g

Inhalation device

Tobramycin inhalation solution: TOBIa

Tobramycin Colistin inhalation inhaled solution: solution Bramitobb

Aztreonam lysine for inhalation solution: Caystonc

Tobramycin Colistin dry dry powder: powder: Podhalerd Colobreathee

300 mg

300 mg

2,000,000 IU (75 mg)

75 mg

112 mg

1,662,500 IUf

5 ml

4 ml

1 ml

1 ml

4 capsules

1 capsule

PARI LChPlus or PARI LC Sprint

k

PARI LC Plus

PARI LC Plus; Altera nebulizer Podhaler system I-nebiAAD; SideStreamj

Colobreatheinhaler device

A–B CFF l recommendation

A–B

I

A–B

A–B

–

Availability

USA, EU, Australia, Asia

USA, EU, Australia, Asia

USA, Canada, EU, Australia

USA, EU, Australia, Asia

UK

USA, EU, Australia, Asia

TOBIÒ, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. b BramitobÒ, Chiesi Limited, Cheadle, UK. CaystonÒ, Gilead Sciences, Inc., Foster City, CA, USA. d PodhalerTM, Novartis Pharmaceuticals Corporation. e ColobreatheÒ,Forest Laboratories UK Ltd., Kent, UK. f Equivalent to 125 mg Colistimethate sodium. g From the Electronic Medicine Compendium [40]. h PARI LCÒ, PARI Respiratory Equipment, Inc., Midlothian, VA, USA. i I-nebÒ, Philips Respironics Inc., Murrysville, PA, USA. j SideStreamÒ, Philips Respironics Inc. k AlteraTM, Gilead Sciences, Inc. l Level of recommendation A for patients with CF over 6 years old with persistent Pseudomonas aeruginosa infection, with moderate to severe disease (FEV1 \70% predicted), B for mild disease (FEV1 C70% predicted) [3] a c

Adv Ther (2015) 32:1–9

3

Fig. 1 Prevalence of bacterial colonization according to age. Reproduced with permission from the UK Cystic Fibrosis Registry Annual data report 2013 [41]. MRSA Methicillin-resistant Staphylococcus aureus pulmonary disease (COPD). In patients with CF, there is an abundance of microorganisms,

negative organisms including P. aeruginosa. They exert their antimicrobial activity by

including anaerobes [4], present in the airways both in the chronic state and during

binding to the 30S subunit of the bacterial ribosome and inhibiting protein synthesis, thus

exacerbations

CF,

inhibiting growth and division of the bacteria.

prevalence of infection of the airways with Pseudomonas aeruginosa increases with age, and

Aminoglycosides are not absorbed enterally, therefore, their administration is parenteral or

by adulthood almost 60% of patients are colonized with P. aeruginosa (Fig. 1). Infection

local. Intravenous aminoglycosides have been widely used for the treatment of infective

with P. aeruginosa has been shown to be associated with a more rapid decline in lung

exacerbations of CF. However, intravenous administration of aminoglycosides is

function and high morbidity and mortality [6–

associated

9]. Exacerbation of CF lung disease is treated with antibiotics targeted against P. aeruginosa,

mainly nephrotoxicity and ototoxicity, and complications and inconvenience related to

usually combining two antibiotics with different mechanisms against Pseudomonas, such as an

the route of administration. Tobramycin, an aminoglycoside, has an enhanced activity

aminoglycoside

antipseudomonal

against P. aeruginosa, with less nephro- and

penicillin, cephalosporin, or a carbapenem [10].

ototoxicity than gentamycin [10]. Tobramycin has been used by inhalation for

INHALED TOBRAMYCIN FOR THE TREATMENT OF LUNG INFECTION IN CF

over two decades, administration has

[5].

and

In

people

an

with

Aminoglycoside antibiotics are valuable tools in the treatment of infections caused by Gram-

with

considerable

and the

side

effects,

this route advantages

of of

achieving high concentrations well above the minimal inhibitory concentration(MIC) at the site of infection, the airways [11], with minimal systemic absorption and hence, fewer systemic

Adv Ther (2015) 32:1–9

4

side effects. Preservative-free preparations of

significant improvement of lung function

tobramycin (TOBIÒ, Novartis Pharmaceuticals

forced expiratory volume in first second (FEV1)

Corporation, East Hanover, NJ, USA, and BramitobÒ, Chiesi Limited, Cheadle, UK) have

after 2 weeks of treatment, and a reduction in the sputum density of P. aeruginosa. Later, it was

been developed and are preferred over intravenous preparations due to less bronchial

demonstrated that an equivalent sputum concentration of tobramycin can be achieved

irritation and a less unpleasant taste [12].

with a lower dose of 300 mg TIS twice daily

Benefits of Inhaled Tobramycin

delivered by a jet nebulizer [19]. In a multicenter study of 520 randomized patients,

When P. aeruginosa infection is first identified,

Ramsey et al. [20] administered 300 mg TIS twice daily intermittently for 28 days on and

early antipseudomonal antibiotics have been shown to successfully eradicate P. aeruginosa

28 days off the drug for a period of 6 months.

colonization, prevent the conversion to chronic

Patients receiving TIS had significant improvement of lung function after 2 weeks of

infection, and improve outcomes. Tobramycin inhalation solution (TIS) has been tested for

treatment, an effect that was maintained throughout the 24-week treatment period,

eradication of P. aeruginosa infection. In the ELITE trial (ClinicalTrials.gov #NCT00391976),

while the placebo group experienced a decline

TIS given twice daily after the new acquisition

in lung function from baseline. TIS-treated patients were 26% less likely to require

of P. aeruginosa was successful in initial eradication from airways in over 90% of

hospitalization and 36% less likely to require intravenous antibiotics for pulmonary

patients when inhaled for 28 or 56 days [13]. In the EPIC trial (ClinicalTrials.gov

exacerbation. P. aeruginosa density was effectively reduced after each cycle of TIS use,

#NCT00097773), TIS was demonstrated to effectively eradicate early P. aeruginosa

although to a lesser extent in advancing

without

treatment cycles. TIS was also found to be safe and effective in reducing P. aeruginosa density in

ciprofloxacin [14]. Other trials have also demonstrated the efficacy of TIS as eradication

children younger than 6 years of age [14]. The beneficial effects of TIS were also demonstrated

treatment as a single agent [15] or when combined with oral ciprofloxacin [16]. A

in improvement of lung imaging abnormalities

infection

when

used

with

or

recent Cochrane analysis using the combined

in an X-ray-based study [21]. In a study comparing TIS to colistin by inhalation, TIS

data from two studies on inhaled tobramycin for eradication of P. aeruginosa found a

was more effective than colistin in decreasing P. aeruginosa density in sputa and in improving

significant benefit of tobramycin over placebo [17].

lung function [22, 23]. However, a later study

The effects of TIS were evaluated in several

demonstrated non-inferiority of colomycin dry powder inhaler over TIS with regard to lung

clinical trials involving patients with CF chronically colonized with P. aeruginosa

function [24]. A final proof of the efficacy of TIS in treatment of patients with CF infected with

infection. In a placebo-crossover study, Ramsey et al. [18] showed a beneficial effect of

P. aeruginosa was the study by Murphy et al.

600 mg

TIS

ultrasonic

twice

daily,

nebulizer,

over

administered placebo,

by

[25], which randomized patients to 28-day cycles of twice-daily TIS or placebo. This study

with

was terminated early after 2 years when an

Adv Ther (2015) 32:1–9

5

interim analysis showed clear benefit to TIS-

testing may actually respond to TIS due to the

treated patients in terms of lung function,

high local concentrations achieved.

number of hospitalizations, and concomitant antibiotic treatment.

of

TIS is administered twice daily by nebulizer. Clinical trials involving TIS used a PARI LCÒ

Inhaled tobramycin was also tested in nonCF bronchiectasis. In those patients, similarly to

nebulizer (PARI Respiratory Equipment, Inc., Midlothian, VA, USA) with a suitable

patients with CF, P. aeruginosa infection is

compressor [14–18], with nebulization times

associated with more rapid lung function decline and more frequent exacerbations [26].

approximating 20 min, excluding time for preparation and for cleaning the nebulizer

Typically, these patients are older than patients with CF with advanced, long-standing disease

after the inhalation. TIS use was also tested with the portable eFlowÒ nebulizer (PARI

and infection, and the effect of inhaled

Respiratory Equipment, Inc.) on six patients

tobramycin was modest in comparison to patients with CF. Patients treated with inhaled

with CF and seven healthy volunteers. Administration time with the eFlow was

tobramycin had fewer hospital admissions and admission days [27–29],and improvement in

significantly shorter than with the PARI LC plus. However, lung deposition was found to be

health-related quality of life [30]. However,

40%

tobramycin-treated patients experienced cough and bronchospasm more frequently than the

difference significant

placebo group [27]. It is possible that people with non-CF bronchiectasis are unable to

improved inhalation system, treatment with inhaled tobramycin, although beneficial,

tolerate the doses used in patients with CF, but lower doses might be tolerated. In these

implicates a considerable load to the already exhausting burden of daily care of patients with

patients, treatment with inhaled tobramycin

CF and may compromise compliance with one

was associated with the development tobramycin-resistant strains [25–28].

or more of the recommended medications [35].

use

of

less

with

the

eFlow,

although

was not considered [34]. However, even

the

clinically with an

TIS is recommended in patients with CF chronically infected with P. aeruginosa [31, 32],

Dry Powder Tobramycin for Inhalation

as grade A recommendation due to a high

The considerations above indicated the need for development of a formulation of tobramycin

certainty of benefit in moderate to severe disease (FEV1 \70%), as a grade B

that

would

simplify

and

shorten

recommendation for patients with mild disease (FEV1 70–89%) [3], and as one of

administration. Attempts with micronizing aminoglycosides preceded the evolution of the

several

spray drying technique, but were generally limited by the need for a large proportion of

therapeutic

alternatives

for

early

eradication of newly acquired P. aeruginosa infection [33]. An important advantage of TIS

carrier molecules and therefore a large number

over intravenous administration of tobramycin is the ability to achieve local concentrations

of inhaled doses required to achieve the required dose in the lungs [31].

which are several fold higher than the MIC [12].

Novartis Pharmaceuticals have developed a formulation of dry powder tobramycin based on

Thus, patients harboring strains of P. aeruginosa that are resistant to tobramycin by sensitivity

emulsification and spray drying [31]. This

Adv Ther (2015) 32:1–9

6

technology consists of emulsification with a

operated and does not require electricity. The

phospholipid, then creating a spray of the

dose of 112 mg is achieved by inhaling four

emulsion by passing it through a thin nozzle with high pressure, and then drying it in hot air.

capsules each time. This dose was found to be equivalent to 300 mg of TIS in a phase II dose-

The process creates a porous sphere (Fig. 2a) which mostly consists of tobramycin and

finding study by Geller et al. [36]. Two phase III clinical trials with the TOBI Podhaler with

phospholipid.

ThesePulmoSphereTM(Novartis

PulmoSphere

technology

have

found

the

Pharmaceuticals Corporation) particles are spherical, relatively uniform in size

formulation comparable to TIS in its clinical efficacy [37, 38].

(1.7–2.7 lm diameter), and, due to the phospholipid outer layer, have a low tendency

In the EVOLVE trial (ClinicalTrials.gov #NCT00125346), 95 patients with CF, aged

to aggregate and form microparticles. Particles

6–21 years with chronic P. aeruginosa infection,

are packaged into capsules, each containing 28 mg tobramycin, the content of which is

were randomized to receive either 112 mg tobramycin inhalation powder (TIP) or placebo

inhaled through a PodhalerTM(Novartis

in the first 28-day cycle (a cycle comprising 28 days on drug, then 28 days off drug),

Corporation;

portable inhaler—the Pharmaceuticals

Fig. 2b)—which

is

breath

followed by two more cycles of open-label TIP [37]. Primary outcome measure was FEV1% predicted, with P. aeruginosa density, MIC to tobramycin, hospitalizations, and use of intravenous antibiotics as secondary outcome measures. The study was terminated early after an interim analysis showed favorable outcomes in the TIP group. FEV1 increased with TIP by a mean of 13% predicted FEV1, and decreased in the placebo group (P = 0.0016). Patients treated with TIP required fewer antibiotics in the first cycle compared to placebo, with no hospitalizations, while 12.2% of the placebo group were hospitalized due to respiratory events in the first cycle. P. aeruginosa density decreased in the TIP group, although TIP use was associated with resistance to tobramycin, with a higher percentage of strains from

Fig. 2 Scanning electron image of the PulmoSphereTM(Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) particle. Tobramycin inhalation powder: a novel, light-porous particle formulation of tobramycin delivered via a simple passive inhaler. a Hollow, porous particles of tobramycin inhalation powder; b the T-326 Inhaler. Reproduced with permission from Konstan et al. [37]

patients in the TIP group having an MIC [8 lg/ml. The administration time of TIP was 4–6 min. The EAGER

trial

(ClinicalTrials.gov

#NCT00388505) tested the non-inferiority of TIP compared to TIS in 553 patients with CF in 127 CF centers which were randomized to 112 mg TIP twice daily through the Podhaler

Adv Ther (2015) 32:1–9

7

versus 300 mg TIS twice daily in 3 treatment

efficacy

cycles (6 months) [38]. Patients were aged

convenience

6 years and older, with an FEV1 between 25% and 75% predicted, and a throat or sputum

reflected in patient questionnaires [38]. The clinical trials involving TIP [37, 38] led

culture with P. aeruginosa within 6 months of study entry. The primary efficacy measure was

to an increasing use of TIP with the Podhaler device among patients with CF. Among the

the change from baseline in FEV1, with

advantages are the ease of administration and

additional outcomes consisting of the change in sputum P. aeruginosa density, P. aeruginosa

shorter time, with maintenance of the advantages of TIS—mostly maintenance of

sensitivity to tobramycin, antibiotic use, and hospitalizations, as well as safety outcomes

lung function and freedom from exacerbations. It is reasonable to assume that

(adverse

shorter

events).

Patients

evaluated

the

and

safety and

to

TIS,

patient

administration

time

with

greater

satisfaction

and

as

ease

of

treatment modalities by a treatment satisfaction questionnaire. FEV1 was similar in

administration of the Podhaler versus TIS will lead to increased compliance with inhaled

the two treatment groups. Adverse events were more common with TIP than TIS, most of

tobramycin, thus improving outcomes for patients with CF [39].

which were mild in severity, mainly cough (48.4% vs. 31.3%, respectively), dysphonia (13.6% vs. 3.8%, respectively), probably due to

CONCLUSIONS

the irritant nature of the dry powder, and dysgeusia (3.9% vs. 0.5%, respectively). Renal

This review summarizes the evidence for the use

and auditory dysfunction occurred with less than 1% of the patients in both treatment groups. Administration time was 5.6 min with TIP versus 15 min with TIS, and satisfaction with treatment was significantly better with TIP. Pharmacokinetics of the drugs in a subset of patients showed similar serum concentrations of tobramycin, with slightly higher sputum concentrations 30 min post-dose on day 28 of the on-cycle, albeit with a large variability between patients (TIP: 1,979 ± 2,770 lg/g; TIS: 1,074 ± 1,182 lg/g). Hospitalization rate was similar

between

the

groups

of inhaled tobramycin in the treatment of chronic P. aeruginosa infection.TIS is highly effective acquired

when used to eradicate newly P. aeruginosa, and in patients

chronically infected with P. aeruginosa, with established efficacy in maintaining function, preventing exacerbations,

lung and

improving survival. TIP is recently introduced alongside TIS. Its advantages are a shorter administration time and portability of its use, with the disadvantage of mild cough and dysphonia. More long-term data are necessary to establish the equivalence of TIP to TIS.

(22–24%).

However, more patients in the TIP group versus the TIS group required antipseudomonal antibiotics (64.9% vs. 54.5%, respectively; P = 0.0148). This effect was mostly

ACKNOWLEDGMENTS

driven by events that required oral antibiotics

No funding or sponsorship was received for this study or publication of this article. During the

and the length of antibiotic treatment tended to be shorter in TIP-treated patients versus the TIS-

peer review process, the manufacturer of the agent under review was offered an opportunity

treated patients. Overall, TIP was comparable in

to comment on the article. Changes resulting

Adv Ther (2015) 32:1–9

8

from comments received were made by the author based on their scientific and editorial merit. All named authors meet the International Committee of Medical Journal

treatment of 2012;7:e45001.

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Kosorok MR, Zeng L, West SE, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32:277–87.

9.

Henry RL, Mellis CM, Petrovic L. Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol. 1992;12:158–61.

visiting research fellow at Queen’s University Belfast with financial support from Novartis Pharmaceuticals. J. Stuart Elborn has undertaken consultancy work for Novartis; all payments were made to Queens University Belfast. Compliance with ethics guidelines. This review is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

One.

Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34:91–100.

approval for the version to be published. Conflict of interest. Michal Shteinberg was a

PLoS

6.

Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final

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