Cystic Fibrosis
New Therapeutics that Target Cystic Fibrosis Symptoms Anti-infectives
Over time, chronic infection and conversion to a mucoid phenotype become dominant, which is associated with poor outcomes. Once established, eradication of Pseudomonas becomes extremely difficult. Therefore, the management of PsA infections generally follows three goals:
Lung infections are extremely common in CF and the repertoire of pathogens is relatively limited and characteristic. In young children, detection of Staphylococcal aureus, a variety of gram-negative rods, and non-typable Hemophilus influenzae in airway cultures is frequent. Over time, Pseudomonas aeruginosa (PsA) becomes the dominant pathogen in CF, with over 80 % of adults with CF demonstrating chronic infection. There is clear evidence that Pseudomonas is associated with decline in lung function, increased symptoms, and a shortened lifespan in CF.47–49
• treatment of pulmonary exacerbations caused by Pseudomonas;
• early eradication of Pseudomonas to prevent chronic infection; and • management of chronic Pseudomonas infection to preserve lung function.
This article focuses on eradication and chronic management of Pseudomonas; the reader is directed towards a recent article summarizing treatment approaches to pulmonary exacerbations in CF.50
Eradication of Pseudomonas aeruginosa
Two recent trials have examined home-based treatments to eradicate PsA. In the Early Pseudomonas Infection Control (EPIC) trial, approximately 300 young patients who were positive for PsA were randomized into two groups, each with two treatment regimens.37,51
The
first group treated patients with nebulized tobramycin solution for inhalation (TSI) or TSI for 28 days + oral ciprofloxacin or placebo for 14 days when oral/pharyngeal (O/P) cultures were positive for PsA. The second arm used a different strategy, in which patients who had positive PsA cultures were treated with TSI or TSI + ciprofloxacin on a cycled basis (quarterly). Preliminary results indicated that all four treatment algorithms produced similar, low-frequency PsA-positive O/P cultures.52 In a related trial conducted in Europe and Canada, children who were PsA-positive were treated with TSI for 28-day (n=45) and 56-day (n=43) cycles. Similar PsA clearance was demonstrated in both treatment groups, with prolonged periods without PsA reacquisition.53
Additional
studies have demonstrated successful eradication of PsA from the CF respiratory tract, supporting aggressive early treatment after detection by surveillance cultures.38,41,54
infection may also be an attainable clinical goal.55
Successful eradication of early mucoid PsA Together, these data
clearly demonstrate that eradication interventions can reduce PsA prevalence in young children and give healthcare providers logical guidance for the treatment of newly acquired infection.
Management of Chronic Pseudomonas aeruginosa Infection TSI (TOBI®, Novartis Pharmaceuticals, Basel, Switzerland) was originally approved for the management of chronic PsA infection in patients over six years of age with a forced expiratory volume in one second (FEV1) between 25 and 75 %.54,56,57
2001, and is typically used in a regular cycled fashion (300mg nebulized 22 Anti-inflammatories
Inflammation in the CF lung is intense, unrelenting, and ultimately damaging to the airways. The dominant cell type is the neutrophil. A variety of alterations in inflammatory signaling have been described in CF that likely contribute to cell influx, including increased interleukin 8 (IL-8) release, nuclear factor kappa B (NFκB)-dependent transcription, IL-17 signaling, altered neutrophil programming, and, possibly, chemotactic fragments derived from structural proteins.67–72
Two agents
have been studied in CF and are believed to provide clinical benefit by reducing lung inflammation (ibuprofen and azithromycin). Ibuprofen was initially studied in a four-year randomized, placebo-controlled trial. Twice-daily dosing to achieve serum levels of 50–100 µg/milliliter
reduced the annual rate of FEV1 decline (–2.17 % compared with –3.60 % in the placebo arm).73
Further subgroup analysis indicated that
the greatest effects were seen in children under 13 years of age. Ibuprofen’s mechanism of action includes inhibition of neutrophil migration into the lungs. Appropriate dosing is required to achieve this beneficial effect. More recently, azithromycin (AZM) has been studied in two separate randomized, placebo-controlled clinical trials of moderate size.74,75
Pseudomonas positive, FEV1 25–75 %) received AZM three times a week for six months. The AZM-treated group demonstrated significant
TSI has been a critical part of CF care since
improvements in lung function (FEV1 treatment difference of 0.094l compared with placebo; p<0.009) that rapidly returned to
US RESPIRATORY DISEASE
twice daily for 28-day on/off cycles) or as a treatment designed to eradicate new acquisitions of PsA. More recently, a second nebulized antibiotic (the monobactam aztreonam lysinate, or Cayston®; Gilead Sciences, Foster City, California, US) has received US Food and Drug Administration (FDA) approval for the treatment of lung infections in CF patients chronically infected with PsA.58–61
The recently completed
Phase III clinical trials of nebulized aztreonam included improvements in patient-reported outcomes (PROs) as a primary outcome measure, focusing on the cystic fibrosis questionnaire (CFQ-R) in the pivotal approval studies.60
Additionally, aztreonam lysine nebulized three times
a day (75 mg) was shown to improve lung function over 28 days of treatment compared with placebo (day 28 treatment difference 10.3 %; p<0.001). Both groups experienced a decline in lung function two weeks after discontinuing treatment, with the intervention group sustaining higher lung function at day 42 (day 42 treatment difference 5.7 %; p<0.002) Aztreonam lysinate is delivered by the Altera nebulizer system, which is portable and completes drug dosing in as little as five minutes. While optimal device performance requires regular cleaning and maintenance, the rapid delivery and portability help to address potential barriers to treatment adherence. There are a number of other nebulized antibiotics in clinical trials for the treatment of CF lung infections, including other aminoglycoside preparations (Tobramycin Powder for Inhalation [TIP], Novartis; Arikace™, Insmed Corp., Monmonth Junction, New Jersey, US, a liposomal-based amikacin preparation), levofloxin (Aeroquin™, Mpex Pharmaceuticals, San Diego, California, US), and combinational antibiotics targeting Pseudomonas and S. aureus (tobramycin and fosfomycin, Gilead).62–66
Thus, the future options for
treatment of CF pulmonary infections with topical antibiotics will likely grow, giving care-givers and patients the opportunity to tailor their treatments to meet specific needs in a personalized fashion.
In the first trial, patients with similar inclusion characteristics to those enrolled into the original TSI trial (over six years of age,
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