Management of Chronic Pseudomonas Aeruginosa Infection with Inhaled Levofloxacin in People with Cystic Fibrosis

Abstract

People with cystic fibrosis (CF) are highly susceptible to bacterial infections of the airways. By adulthood, chronic Pseudomonas aeruginosa ( Pa) is the most prevalent infective organism and is difficult to eradicate owing to its adaptation to the CF lung microenvironment. Long-term suppressive treatment with inhaled antimicrobials is the standard care for reducing exacerbation frequency, improving quality of life and increasing measures of lung function. Levofloxacin (a fluoroquinolone antimicrobial) has been approved as an inhaled solution in Europe and Canada, for the treatment of adults with CF with chronic P. aeruginosa pulmonary infections. Here, we review the clinical principles relating to the use of inhaled antimicrobials and inhaled levofloxacin for the management of P. aeruginosa infections in patients with CF.

Antibiotic resistance in chronic respiratory diseases: from susceptibility testing to the resistome

“…The resistome has an impact on the phenotypic antibiotic bacterial resistance, which is also affected by lung environment factors such as airway mucus composition, biofilm formation, bacterial interactions, human genetics and the immune response. [16,[20][21][22]] Continuous daily administration mode also increasingly recommended [23] Maintenance therapy Proposition of 6 months of oral azithromycin with a 3 times a week dose of 500 mg [27] Key pathogens Antibiotic courses administered 3 times per week [24]…”

Differential Performance and Lung Deposition of Levofloxacin with Different Nebulisers Used in Cystic Fibrosis

“…Clinical trials have demonstrated a significant improvement in lung function and a reduction in the exacerbation rate with inhaled levofloxacin against placebo [ 16 , 17 ] and equivalent outcomes compared with tobramycin in adult patients with CF [ 18 ]. Levofloxacin belongs to the fluoroquinolone antibiotic class and displays broad-spectrum activity against Gram-negative and Gram-positive bacteria, disrupting the bacterial DNA synthesis through inhibitory interactions with the DNA gyrase and topoisomerase IV enzymes [ 5 , 19 ]. The efficacy spectrum and mechanism of action of levofloxacin are different from the previously approved inhaled antipseudomonal antibiotics (tobramycin, colistin, and aztreonam).…”

“…Once that bacterial colonisation with Pseudomonas aeruginosa is established, complete eradication is difficult to achieve [ 3 ], and the disease progresses to a state of chronic infection with concomitant inflammation and lung remodelling that produces structural changes and progressive, life-threatening deterioration of lung function [ 4 ]. Pseudomonas aeruginosa infections are predominant in adulthood and are a major cause of morbidity and mortality in people with CF [ 5 ].…”

“…These factors may lead to off-label uses of nebulisers due to device preference or availability. In recent years, optimised drug-device combinations with vibrating membrane nebulisers have been approved for several inhaled antibiotics such as aztreonam, amikacin, and levofloxacin [ 5 , 13 , 14 ]. The off-label use of general-purpose nebulisers with these novel antibiotic formulations may have unpredictable results, potentially delivering either subtherapeutic doses with low-efficiency devices or toxic drug concentrations with highly efficient smart nebulisers.…”

“…Levofloxacin is the first fluoroquinolone approved for inhalation in CF, providing an alternative mechanism of action to combat P. aeruginosa infections that complements the previously approved antibiotics for this indication: tobramycin, colistin, and aztreonam [ 6 ]. The dosage of inhaled levofloxacin is 240 mg (2.4 mL at 100 mg/mL) twice daily delivered with its drug-specific nebuliser Zirela in alternating cycles of 28 days on/off therapy [ 5 ]. We have recently shown that Zirela delivers respirable levofloxacin aerosols with a mass median aerodynamic diameter (MMAD) of 3.56 μm, requiring less than 5 min to deliver a full levofloxacin dose [ 15 ].…”