Antibiotics In Cystic Fibrosis Research Articles

P269 Proposed plan for oxygen therapy as an adjuvant to antibiotics in cystic fibrosis

Although the use of modulator treatments targeting the basal defect in the Cystic Fibrosis transmembrane conductance regulator improves lung function and is associated with reduced burden of lung infections, we have not seen bacterial eradication, thus antibiotic treatments remain crucial for targeting chronic Pseudomonas aeruginosa infection. Recent investigations have shown large zones of oxygen (O2) depletion in the infected part of CF lungs due to consumption of O2 by the surrounding neutrophils, where bacterial aerobic respiration is prevented. The restriction of O2 causes reduced uptake of antibiotics, down-regulation of antibiotic targets and inhibited induction of bactericidal amounts of reactive O2 species as seen for P. aeruginosa. By enhancing the aerobic physiology of the bacteria through adjuvant O2 treatment with normobaric O2 treatment (NBOT), the bacteria can be sensitized, and even clones, protected by the O2 depletion, can be treated. We hypothesize that adjuvant intermittent normobaric oxygenation (100% O2) has a beneficiary clinical impact on chronic P. aeruginosa lung infection.

P252 Proposed plan for oxygen therapy as an adjuvant to antibiotics in cystic fibrosis

There is a clear need for new antibiotics to improve the efficacy of long-term antimicrobial therapy in pwCF. Cefiderocol is currently licensed for the treatment of infections due to Gram-negative organisms with limited treatment options. The aim of this study was to determine the susceptibility of a broad range of CF Gram-negative pathogens to cefiderocol and relevant comparator antibiotics.

Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis

BackgroundTreatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations. MethodsProspective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites. ResultsAzithromycin maximum concentration (Cmax ) was higher and rifampin Cmax was lower in fasting CF subjects compared to HC, while other PK measures, including those for ethambutol, were similar. Addition of food and enzymes did not improve the Cmax of the antimycobacterial drugs. Nineteen of 20 CF subjects had one or more abnormal Cmax z-scores in either the fasting or fed state (or both), when compared to HC. ConclusionPK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin Cmax was slightly higher in people with CF after a single dose. Rifampin PK parameters were altered in persons with CF. Addition of food and enzymes in CF subjects did not improve PK parameters. Standard dosing guidelines should be used as a starting point for people with CF initiating MAC therapy and therapeutic drug monitoring should be routinely performed to prevent the possibility of treatment failure due to abnormal drug concentrations. Clinical trial registrationClinicalTrials.gov Identifier: NCT02372383Prior abstract publication:1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017.2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52–53, 2017.

Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities.

Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities.

Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis.

The pharmacokinetics (PK) of β-lactam antibiotics in cystic fibrosis (CF) patients has been compared with that in healthy volunteers for over four decades; however, no quantitative models exist that explain the PK differences between CF patients and healthy volunteers in older and newer studies. Our aims were to critically evaluate these studies and explain the PKdifferences between CF patients and healthy volunteers. We reviewed all 16 studies that compared the PK of β-lactams between CF patients and healthy volunteers within the same study. Analysis of covariance (ANCOVA) models were developed. In four early studies that compared adolescent, lean CF patients with adult healthy volunteers, clearance (CL) in CF divided by that in healthy volunteers was 1.72 ± 0.90 (average ± standard deviation); in four additional studies comparing age-matched (primarily adult) CF patients with healthy volunteers, this ratio was 1.46 ± 0.16. The CL ratio was 1.15 ± 0.11 in all eight studies that compared CF patients and healthy volunteers who were matched in age, body size and body composition, or that employed allometric scaling by lean body mass (LBM). Volume of distribution was similar between subject groups after scaling by body size. For highly protein-bound β-lactams, the unbound fraction was up to 2.07-fold higher in older studies that compared presumably sicker CF patients with healthy volunteers. These protein-binding differences explained over half of the variance for the CL ratio (p <0.0001, ANCOVA). Body size, body composition and lower protein binding in presumably sicker CF patients explained the PK alterations in this population. Dosing CF patients according to LBM seems suitable to achieve antibiotic target exposures.

WS12.3 Telehealth monitoring for home intravenous antibiotics in cystic fibrosis

WS12.3 Telehealth monitoring for home intravenous antibiotics in cystic fibrosis

Delivering drugs to the lungs: The history of repurposing in the treatment of respiratory diseases

The repurposing of drug delivery by the pulmonary route has been applied to treatment and prophylaxis of an increasingly wide range of respiratory diseases. Repurposing has been most successful for the delivery of inhaled bronchodilators and corticosteroids in patients with asthma and chronic obstructive pulmonary disease (COPD). Repurposing utilizes the advantages that the pulmonary route offers in terms of more targeted delivery to the site of action, the use of smaller doses, and a lower incidence of side-effects. Success has been more variable for other drugs and treatment indications. Pulmonary delivery is now well established for delivery of inhaled antibiotics in cystic fibrosis (CF), and in the treatment of pulmonary arterial hypertension (PAH). Other inhaled treatments such as those for idiopathic pulmonary fibrosis (IPF), lung transplant rejection or tuberculosis may also become routine. Repurposing has progressed in parallel with the development of new drugs, inhaler devices and formulations.

How to Manage Antibiotic Allergy in Cystic Fibrosis? Epidemiologic, Diagnostic, and Therapeutic Aspects

Cystic fibrosis (CF) is a complex genetic disease with high mortality, of which 85% is a result of lung disease characterized by serious endobronchial infections. Antibiotic therapy is one of the main treatments of CF, both during acute exacerbations and as chronic maintenance medications, contributing to a prolonged survival. Since neonatal CF screening programs have been implemented universally and the longevity of patients with CF steadily increases, antibiotic hypersensitivity reactions (HSRs) are becoming more important. HSR to antibiotics in CF has been reported since the 1980s and was estimated to occur up to three times more frequently in these patients, probably owing to high rates of antibiotic exposure and boosting stimuli such as infections and inflammation. However, recent studies including large groups of CF patients with a suspicion of antibiotic allergy have used diagnostic algorithms including skin tests and drug provocation tests and showed that true incidence was much lower. The mechanism of the reactions and the clinical presentations are not different in CF than in the general population. Both the immediate and nonimmediate type HSRs are seen, and among the latter, drug fever and drug-induced hemolytic anemia are distinctive presentations. Beta-lactam (BL) agents are the most common cause, with higher rates for ureidopenicillins (piperacillin, mezlocillin, and piperacillin/tazobactam) and cephalosporins (especially ceftazidime), intermediate rates for carbapenems, and lowest rates for aztreonam, and also HSRs to aminoglycosides, macrolides, and quinolones are encountered. Since the available choices for antibiotic therapy are limited due to relevant organisms, management becomes a challenge. It is essential to evaluate the patients according to the mechanism of the HSR and determine the risk of repeat administration of the culprit drug and also safety of alternative drugs with prior skin and provocation tests. The chemical structure and side chains must be taken into account when selecting a safe alternative drug. Contrary to what was previously thought, recent data on cross-reactions between BL antibiotics showed that some BLs can be an option of treatment for patients allergic to other BLs. Desensitization is a useful procedure in immediate and some delayed reactions, if a suitable alternative antibiotic is not available.

Daily spirometry in an acute exacerbation of adult cystic fibrosis patients.

To help answer the question of length of intravenous antibiotics during an acute exacerbation of cystic fibrosis (CF), we had subjects to follow daily home spirometry while on intravenous antibiotics. CF patients, 18 and older, with an acute exacerbation requiring intravenous antibiotics had a daily FEV1. The average time to a 10% increase over their initial sick FEV1 was calculated, as well as the time to a new baseline. A total of 25 subjects completed the study. Ten of the 25 subjects did not have a sustainable 10% increase in FEV1. Of the 15 subjects with a sustainable 10% increase in FEV1, it took 5.2 days (±4.5) after day 1, while a new baseline was achieved on average at 6.6 days (±4.8) after day 1. Given the wide range of time to a 10% improvement and new baseline, it is recommended there should be flexibility in length of intravenous antibiotics in CF, not by a preset number.

EPS7.1 IgE-mediated and lymphocytic sensitization to antibiotics in cystic fibrosis

EPS7.1 IgE-mediated and lymphocytic sensitization to antibiotics in cystic fibrosis

EPS7.2 Pharmacokinetics of oral MAC antibiotics in cystic fibrosis

EPS7.2 Pharmacokinetics of oral MAC antibiotics in cystic fibrosis

Polyanion-tobramycin nanocomplexes into functional microparticles for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis.

Efficacy of antibiotics in cystic fibrosis (CF) is compromised by the poor penetration through mucus barrier. This work proposes a new 'nano-into-micro' approach, used to obtain a combinatorial effect: achieve a sustained delivery of tobramycin and overcome mucus barrier. Mannitol microparticles (MPs) were loaded with a tobramycin polymeric nanocomplex and characterized in presence of CF artificial mucus. MPs are able to alter the rheological properties of CF artificial mucus, enhancing drug penetration into it and allowing a prolonged drug release. MPs resulted to be effective in Pseudomonas aeruginosa infections if compared with free tobramycin. MPs resulted to be a formulation of higher efficacy, with potential positive implications, as lower required dose, administration frequency, side effects and antibiotic resistance problems.

Sequential Treatment of Biofilms with Aztreonam and Tobramycin Is a Novel Strategy for Combating Pseudomonas aeruginosa Chronic Respiratory Infections.

Traditional therapeutic strategies to control chronic colonization in cystic fibrosis (CF) patients are based on the use of a single nebulized antibiotic. In this study, we evaluated the therapeutic efficacy and dynamics of antibiotic resistance in Pseudomonas aeruginosa biofilms under sequential therapy with inhaled aztreonam (ATM) and tobramycin (TOB). Laboratory strains PAO1, PAOMS (hypermutable), PAOMA (mucoid), and PAOMSA (mucoid and hypermutable) and two hypermutable CF strains, 146-HSE (Liverpool epidemic strain [LES-1]) and 1089-HSE (ST1089), were used. Biofilms were developed using the flow cell system. Mature biofilms were challenged with peak and 1/10-peak concentrations of ATM (700 mg/liter and 70 mg/liter), TOB (1,000 mg/liter and 100 mg/liter), and their alternations (ATM/TOB/ATM and TOB/ATM/TOB) for 2 (t = 2), 4 (t = 4), and 6 days (t = 6). The numbers of viable cells (CFU) and resistant mutants were determined. Biofilm structural dynamics were monitored by confocal laser scanning microscopy and processed with COMSTAT and IMARIS software programs. TOB monotherapy produced an intense decrease in CFU that was not always correlated with a reduction in biomass and/or a bactericidal effect on biofilms, particularly for the CF strains. The ATM monotherapy bactericidal effect was lower, but effects on biofilm biomass and/or structure, including intense filamentation, were documented. The alternation of TOB and ATM led to an enhancement of the antibiofilm activity against laboratory and CF strains compared to that with the individual regimens, potentiating the bactericidal effect and/or the reduction in biomass, particularly at peak concentrations. Resistant mutants were not documented in any of the regimens at the peak concentrations and only anecdotally at the 1/10-peak concentrations. These results support the clinical evaluation of sequential regimens with inhaled antibiotics in CF, as opposed to the current maintenance treatments with just one antibiotic in monotherapy.

Inhaled antibiotics for the treatment of chronic Pseudomonas aeruginosa infection in cystic fibrosis patients: challenges to treatment adherence and strategies to improve outcomes.

BackgroundInhaled antibiotics (ABs) are recommended for use in the therapy of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF). The aim of this systematic literature review was to identify level of adherence to inhaled ABs and to determine predictors and consequences of nonadherence in CF.MethodsA systematic literature search of English-language articles was conducted in April 2015 using Medline and Embase. No publication date limit was applied. The literature screening was conducted by two independent reviewers. All of the included studies were assessed for quality.ResultsThe search yielded 193 publications, of which ten met the inclusion criteria and underwent data extraction. Seven studies focused on inhaled tobramycin, one on inhaled colistimethate, one on inhaled levofloxacin, and one on inhaled aztreonam lysine. Medication adherence to inhaled ABs was analyzed by pharmacy refill history, daily phone diary, parent and child self-reports, vials counting, or electronic monitoring. In randomized controlled trials (n=3), proportion of adherent patients (>75%–80% of required doses taken) ranged from 86% to 97%; in prospective cohort studies (n=3), adherence rates ranged between 36% and 92%, and in retrospective studies (n=4) it ranged between 60% and 70%. The adherence to inhaled ABs in CF was found to be associated with the complexity of treatment, time of drug administration, age of patients, treatment burden (adverse events, taste), and patient satisfaction.ConclusionThe high diversity of adherence data was because of the different study designs (randomized controlled trials vs real-world studies) and the lack of a commonly accepted consensus on the definition of adherence in the reviewed articles. Routine adherence monitoring during CF care, discussing the possible reasons of suboptimal adherence with the patient, and changing treatment regimens on the basis of patient burden can individualize CF therapy for patients and may improve the level of adherence.

Serum Iron Level Is Associated with Time to Antibiotics in Cystic Fibrosis.

Serum levels of hepcidin-25, a peptide hormone that reduces blood iron content, are elevated when patients with cystic fibrosis (CF) develop pulmonary exacerbation (PEx). Because hepcidin-25 is unavailable as a clinical laboratory test, we questioned whether a one-time serum iron level was associated with the subsequent number of days until PEx, as defined by the need to receive systemic antibiotics (ABX) for health deterioration. Clinical, biochemical, and microbiological parameters were simultaneously checked in 54 adults with CF. Charts were reviewed to determine when they first experienced a PEx after these parameters were assessed. Time to ABX was compared in subgroups with and without specific attributes. Multivariate linear regression was used to identify parameters that significantly explained variation in time to ABX. In univariate analyses, time to ABX was significantly shorter in subjects with Aspergillus-positive sputum cultures and CF-related diabetes. Multivariate linear regression models demonstrated that shorter time to ABX was associated with younger age, lower serum iron level, and Aspergillus sputum culture positivity. Serum iron, age, and Aspergillus sputum culture positivity are factors associated with shorter time to subsequent PEx in CF adults.

Inhaled antibiotics in Cystic Fibrosis (CF) and non-CF bronchiectasis.

Bronchiectasis is a pathological diagnosis describing dilatation of the airways and is characterized by chronic lung sepsis. Bronchiectasis has multiple etiologies, but is usually considered in terms of whether it is due to the genetic disorder cystic fibrosis (CF) or secondary to other causes (non-CF bronchiectasis, NCFB). Inhaled antibiotics are used in bronchiectasis to suppress bacterial pathogens and reduce long-term lung function decline. The majority of the literature on inhaled antibiotics comes from studies on CF where the dominant bacterial pathogen in the airway is usually Pseudomonas aeruginosa. Thus, most aerosolized antibiotic regimens target this bacterium, but the emergence of molecular diagnostic methods has questioned this approach and more tailored strategies may need to be considered in CF based on the community composition of the lung microbiome. Similarly, the lung microbiome in NCFB has been found to be a complex polymicrobial one and the current practice of employing the same inhaled antibiotic regimes as are used in CF may no longer be appropriate in many patients. In this article, the use of inhaled antibiotics in CF and NCFB is considered in the light of improved understanding of the lung microbiome and why more tailored therapy may be needed based on molecular identification of the microbial pathogens present. The evidence for the use of currently available inhaled antibiotics and advances in inhaled drug packaging and delivery devices are discussed. Finally, the urgent need for prospective randomized clinical trials in CF and NCFB is highlighted and areas for future research identified.

Emerging Opportunities for Inhaled Antibiotic Therapy

Inhaled antibiotics have become a mainstay of cystic fibrosis (CF) therapy by providing high drug concentrations locally in the lung while minimizing systemic exposure and thus the potential for side effects. In CF, inhaled antibiotics decrease the rate of decline of lung function, improve the quality of life, and reduce the frequency of exacerbations and hospital admissions. However, the burden of therapy remains high in CF. There is an opportunity for more convenient and effective inhaled antibiotics to reduce the disease burden in CF. In contrast, despite the unmet medical need, no inhaled antibiotics are approved for lung infections in a number of other diseases including non-CF bronchiectasis, COPD, melioidosis, pneumonic plague, anthrax, Qfever, tularemia and patients with other infections including non-tuberculous mycobacteria. This review discusses the progress towards achieving that goal in those indications. Additionally, the approved inhaled antibiotics in CF are only available as a fixed dose that is inhaled twice or thrice daily. There is a limited opportunity to personalize therapy to the patient. This review envisions a future scenario where the treatment of lung infections can be optimized to the specific needs of each individual based on the attributes of their infectious agents.

Inhaled antibiotics in cystic fibrosis: what's new?

Cystic Fibrosis is an autosomal recessive inheritable condition principally involving the lungs, pancreas, liver and intestines. Pulmonary involvement is characterized by airway inflammation and infection starting at an early age1,2 and is the primary cause of premature death.3 This paper will review the current situation in terms of prevalence of bacterial pathogens causing pulmonary infections and the strategies currently employed to treat these infections, focusing primarily on inhaled antibiotic therapy. This will be followed by a review of newly introduced inhaled antibiotics and of those in development.

66 Efficacy of tobramycin inhalation powder (TIP) versus other inhaled antibiotics in cystic fibrosis (CF) patients with chronic P. aeruginosa infection: a network meta-analysis

66 Efficacy of tobramycin inhalation powder (TIP) versus other inhaled antibiotics in cystic fibrosis (CF) patients with chronic P. aeruginosa infection: a network meta-analysis

Increasing resistance of the Liverpool Epidemic Strain (LES) of Pseudomonas aeruginosa (Psa) to antibiotics in cystic fibrosis (CF)—A cause for concern?

BackgroundTransmissible Pseudomonas aeruginosa (Psa) strains such as the Liverpool Epidemic Strain (LES) are now widespread throughout UK CF clinics: their susceptibility to antibiotics is therefore important. To study this, we compared antibiogram patterns of Psa strains in our CF clinic over 5years, looking at differences in resistance patterns between strains and changes to these over time. MethodsThe antibiograms of sputum samples between 2004 and 2008 from patients attending our centre were included. We compared Psa isolate antibiotic resistance (to six anti-pseudomonal antibiotics) patterns for patients infected with LES with those infected with other Psa strains, both in the total population in 2004 (125 patients) and 2008 (166 patients) and also longitudinally from annual review samples 2004 to 2008 in matched and unmatched patient groups. ResultsLES exhibited significantly more resistant isolates in 2004 (p<0.0001). There was an increase in antibiotic resistance in both LES and other Psa strains over time (p<0.001). Cox proportional hazards analysis of both unmatched (n=125) and matched (n=56) patients in 2004 revealed that LES infected patients were more likely to develop antibiotic resistant isolates over time (hazard ratio 8.1, p<0.001). Fewer LES isolates were classed as fully sensitive in both matched and unmatched groups at the end of study period (p<0.001). ConclusionThis study shows a worrying trend in antibiotic resistance in the Psa isolates amongst patients chronically infected with LES. This highlights the need to prevent cross infection through segregation and also the need to develop new strategies to treat these organisms.