Review
Aerosolized antibiotics in cystic fibrosis: an update Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 02/01/15 For personal use only.
Expert Rev. Respir. Med. 8(3), 305–314 (2014)
Stanley B Fiel Morristown Medical Center/Atlantic Health System, 100 Madison Avenue, Morristown, NJ 07960, USA Tel.: +1 973 971 5136 Fax: +1 973 290 8325 [email protected]
Inhaled antibiotic therapy, targeting Pseudomonas aeruginosa, is a fundamental component of cystic fibrosis (CF) management. Tobramycin inhalation solution (TIS) was approved in the United States (US) in 1998. Subsequent research efforts focused on developing products with a reduced treatment time burden. Aztreonam for inhalation solution (AZLI), administered via a more efficient nebulizer than TIS, was approved in the US in 2010. Dry powder for inhalation (DPI) formulations provide alternatives to nebulized therapy: tobramycin powder for inhalation (also known as TIPTM ) was approved in the US in 2013, and colistimethate sodium DPI received European approval in 2012. Other aerosolized antibiotics and regimens combining inhaled antibiotics are in development. Inhaled antibiotic rotation (e.g., TIS alternating with AZLI) is an important concept being actively tested in CF. KEYWORDS: aerosolized antibiotic • aztreonam lysine • colistimethate sodium • cystic fibrosis • dry powder for inhalation • inhaled solution • Pseudomonas aeruginosa • tobramycin
Cystic fibrosis (CF) is characterized by the production of thick mucus in the lungs and other mucus-secreting organs. In the natural history of CF, a myriad of complications may develop in the respiratory, pancreatic, hepatobiliary, gastrointestinal, renal, endocrine and/ or genitourinary systems [1]. The median survival of patients with CF is approximately 37 years for children born during 2007–2011, representing an increase of almost 10 years compared with 1987–1991 data [2]. It is estimated that over 90% of deaths due to CF are attributable to lung disease, the culmination of early and persistent infections that lead to structural changes over time, progressive airway obstruction and ultimately respiratory failure [1]. Most intermittent episodes of acute worsening of symptoms, referred to as acute pulmonary exacerbations, require medical intervention with antibiotics [3]. Inhaled antibiotic therapy, aimed at preserving lung function as well as reducing exacerbation risk, plays a key role in mitigating the risks associated with lung infections in CF. High payloads of antibiotics delivered topically are capable of achieving infection site concentrations beyond those possible with oral or intravenous (iv.) antibiotics. The typical microbiology of lung infection in CF by age is illustrated in FIGURE 1 [2]. With some pathogens, such as Staphylococcus aureus and Haemophilus influenzae, the proportions of informahealthcare.com
10.1586/17476348.2014.896205
patients with detectable organisms increase during the early years of life, but subsequently fall in a gradual manner (starting in adulthood for the former and during childhood for the latter). Conversely, the prominence of Pseudomonas aeruginosa colonization increases with age, with estimated prevalence rates of >20% in infants and preschoolers, >40% in preteens and adolescents and >60% in adults (and approaching 80% in patients aged 25–44 years) [2]. This paper provides an update on the use of aerosolized antibiotics and devices in the treatment of P. aeruginosa-associated CF lung disease, focusing on new developments since the publication of an earlier review of this topic [4]. Aerosolized antibiotics for CF
The biochemical aspects of importance for aerosolized antibiotics in the treatment of CF include microbial spectrum, pharmacokinetics and pharmacodynamics, as previously reviewed [4]. It is critical that a given antibiotic targets the underlying pathogen of interest (P. aeruginosa or otherwise) via a practical dosing regimen that maximizes efficacy, while minimizing local toxicity and the risk of systemic effects. Particle size and pulmonary bioavailability are key pharmacokinetic aspects of aerosolized antibiotics; pharmacodynamic considerations include the
2014 Informa UK Ltd
ISSN 1747-6348
305
Review
Fiel
80
Percent of people with CF
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 02/01/15 For personal use only.
S. aureus‡
P. aeruginosa†
S. aureus‡ 67.9% H. influenzae 16.5%
60
S. maltophilia 14.0% MDR-PA 9.1% 40 H. influenzae
P. aeruginosa† 50.6%
MRSA
MRSA 25.9% MDR-PA
20
B. cepacia complex 2.6%
Achromobacter 0
Achromobacter xylosoxidans 6.2%
S. maltophilia
Aerosolized antibiotics in cystic fibrosis: an update Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 02/01/15 For personal use only.
Expert Rev. Respir. Med. 8(3), 305–314 (2014)
Stanley B Fiel Morristown Medical Center/Atlantic Health System, 100 Madison Avenue, Morristown, NJ 07960, USA Tel.: +1 973 971 5136 Fax: +1 973 290 8325 [email protected]
Inhaled antibiotic therapy, targeting Pseudomonas aeruginosa, is a fundamental component of cystic fibrosis (CF) management. Tobramycin inhalation solution (TIS) was approved in the United States (US) in 1998. Subsequent research efforts focused on developing products with a reduced treatment time burden. Aztreonam for inhalation solution (AZLI), administered via a more efficient nebulizer than TIS, was approved in the US in 2010. Dry powder for inhalation (DPI) formulations provide alternatives to nebulized therapy: tobramycin powder for inhalation (also known as TIPTM ) was approved in the US in 2013, and colistimethate sodium DPI received European approval in 2012. Other aerosolized antibiotics and regimens combining inhaled antibiotics are in development. Inhaled antibiotic rotation (e.g., TIS alternating with AZLI) is an important concept being actively tested in CF. KEYWORDS: aerosolized antibiotic • aztreonam lysine • colistimethate sodium • cystic fibrosis • dry powder for inhalation • inhaled solution • Pseudomonas aeruginosa • tobramycin
Cystic fibrosis (CF) is characterized by the production of thick mucus in the lungs and other mucus-secreting organs. In the natural history of CF, a myriad of complications may develop in the respiratory, pancreatic, hepatobiliary, gastrointestinal, renal, endocrine and/ or genitourinary systems [1]. The median survival of patients with CF is approximately 37 years for children born during 2007–2011, representing an increase of almost 10 years compared with 1987–1991 data [2]. It is estimated that over 90% of deaths due to CF are attributable to lung disease, the culmination of early and persistent infections that lead to structural changes over time, progressive airway obstruction and ultimately respiratory failure [1]. Most intermittent episodes of acute worsening of symptoms, referred to as acute pulmonary exacerbations, require medical intervention with antibiotics [3]. Inhaled antibiotic therapy, aimed at preserving lung function as well as reducing exacerbation risk, plays a key role in mitigating the risks associated with lung infections in CF. High payloads of antibiotics delivered topically are capable of achieving infection site concentrations beyond those possible with oral or intravenous (iv.) antibiotics. The typical microbiology of lung infection in CF by age is illustrated in FIGURE 1 [2]. With some pathogens, such as Staphylococcus aureus and Haemophilus influenzae, the proportions of informahealthcare.com
10.1586/17476348.2014.896205
patients with detectable organisms increase during the early years of life, but subsequently fall in a gradual manner (starting in adulthood for the former and during childhood for the latter). Conversely, the prominence of Pseudomonas aeruginosa colonization increases with age, with estimated prevalence rates of >20% in infants and preschoolers, >40% in preteens and adolescents and >60% in adults (and approaching 80% in patients aged 25–44 years) [2]. This paper provides an update on the use of aerosolized antibiotics and devices in the treatment of P. aeruginosa-associated CF lung disease, focusing on new developments since the publication of an earlier review of this topic [4]. Aerosolized antibiotics for CF
The biochemical aspects of importance for aerosolized antibiotics in the treatment of CF include microbial spectrum, pharmacokinetics and pharmacodynamics, as previously reviewed [4]. It is critical that a given antibiotic targets the underlying pathogen of interest (P. aeruginosa or otherwise) via a practical dosing regimen that maximizes efficacy, while minimizing local toxicity and the risk of systemic effects. Particle size and pulmonary bioavailability are key pharmacokinetic aspects of aerosolized antibiotics; pharmacodynamic considerations include the
2014 Informa UK Ltd
ISSN 1747-6348
305
Review
Fiel
80
Percent of people with CF
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 02/01/15 For personal use only.
S. aureus‡
P. aeruginosa†
S. aureus‡ 67.9% H. influenzae 16.5%
60
S. maltophilia 14.0% MDR-PA 9.1% 40 H. influenzae
P. aeruginosa† 50.6%
MRSA
MRSA 25.9% MDR-PA
20
B. cepacia complex 2.6%
Achromobacter 0
Achromobacter xylosoxidans 6.2%
S. maltophilia
