Systematic Comparison of the Population Pharmacokinetics and Pharmacodynamics of Piperacillin in Cystic Fibrosis Patients and Healthy Volunteers

ABSTRACT Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 ± 7.8 kg) and 26 healthy volunteers (WT, 71.1 ± 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (≥90%) probability-of-target attainment (PTA) for MICs of ≤12 mg/liter in CF patients and ≤16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of ≤16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.

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Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01484-10 ◽

2011 ◽

Vol 55 (6) ◽

pp. 2927-2936 ◽

Cited By ~ 8

Author(s):

J. B. Bulitta ◽

M. Kinzig ◽

C. B. Landersdorfer ◽

U. Holzgrabe ◽

U. Stephan ◽

...

Keyword(s):

Cystic Fibrosis ◽

Healthy Volunteers ◽

High Performance ◽

Standard Dose ◽

Total Body Weight ◽

Volume Of Distribution ◽

Nonparametric Bootstrap ◽

Population Pk ◽

Total Body ◽

Similar Body

ABSTRACTCystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] = 45.7 kg) and 12 healthy volunteers (LBM = 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC ≥ 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (P≤ 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs ≤ 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs ≤ 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs ≤ 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.

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Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00936-09 ◽

2010 ◽

Vol 54 (3) ◽

pp. 1275-1282 ◽

Cited By ~ 31

Author(s):

J. B. Bulitta ◽

C. B. Landersdorfer ◽

S. J. Hüttner ◽

G. L. Drusano ◽

M. Kinzig ◽

...

Keyword(s):

Cystic Fibrosis ◽

Healthy Volunteers ◽

Burkholderia Cepacia ◽

Total Body Weight ◽

Volume Of Distribution ◽

Fat Free Mass ◽

Population Pharmacokinetic ◽

Total Clearance ◽

Target Time ◽

Population Pk

ABSTRACT Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF patients (total body weight [WT] [average ± standard deviation] = 42.9 ± 18.4 kg) and seven healthy volunteers (WT = 66.2 ± 4.9 kg) received 2 g ceftazidime as a 5-min intravenous infusion. High-performance liquid chromatography (HPLC) was used for drug analysis, and NONMEM (results reported), S-ADAPT, and NPAG were used for parametric and nonparametric population PK modeling. We considered linear and allometric body size models to scale clearance and volume of distribution. Monte Carlo simulations were based on a target time of non-protein-bound plasma concentration of ceftazidime above MIC of ≥65%, which represents near-maximal killing. Unscaled total clearance was 19% lower in CF patients, and volume of distribution was 36% lower. Total clearance was 7.82 liters/h for CF patients and 6.68 liters/h for healthy volunteers with 53 kg fat-free mass. Allometric scaling by fat-free mass reduced the between-subject variability by 32% for clearance and by 18 to 26% for volume of both peripheral compartments compared to linear scaling by WT. A 30-min ceftazidime infusion of 2 g/70 kg WT every 8 h (q8h) achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤1 mg/liter in CF patients and ≤3 mg/liter in healthy volunteers. Alternative modes of administration achieved robust PTAs up to markedly higher MICs of ≤8 to 12 mg/liter in CF patients for 5-h infusions of 2 g/70 kg WT q8h and ≤12 mg/liter for continuous infusion of 6 g/70 kg WT daily.

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Cystic Fibrosis Sputum Impairs the Ability of Neutrophils to Kill Staphylococcus aureus

Pathogens ◽

10.3390/pathogens10060703 ◽

2021 ◽

Vol 10 (6) ◽

pp. 703

Author(s):

Kayla Fantone ◽

Samantha L. Tucker ◽

Arthur Miller ◽

Ruchi Yadav ◽

Eryn E. Bernardy ◽

...

Keyword(s):

Cystic Fibrosis ◽

Staphylococcus Aureus ◽

Healthy Volunteers ◽

Airway Disease ◽

Neutrophil Extracellular Trap ◽

Lung Function Decline ◽

Bacterial Killing ◽

Cystic Fibrosis Sputum ◽

Microbial Infections

Cystic fibrosis (CF) airway disease is characterized by chronic microbial infections and infiltration of inflammatory polymorphonuclear (PMN) granulocytes. Staphylococcus aureus (S. aureus) is a major lung pathogen in CF that persists despite the presence of PMNs and has been associated with CF lung function decline. While PMNs represent the main mechanism of the immune system to kill S. aureus, it remains largely unknown why PMNs fail to eliminate S. aureus in CF. The goal of this study was to observe how the CF airway environment affects S. aureus killing by PMNs. PMNs were isolated from the blood of healthy volunteers and CF patients. Clinical isolates of S. aureus were obtained from the airways of CF patients. The results show that PMNs from healthy volunteers were able to kill all CF isolates and laboratory strains of S. aureus tested in vitro. The extent of killing varied among strains. When PMNs were pretreated with supernatants of CF sputum, S. aureus killing was significantly inhibited suggesting that the CF airway environment compromises PMN antibacterial functions. CF blood PMNs were capable of killing S. aureus. Although bacterial killing was inhibited with CF sputum, PMN binding and phagocytosis of S. aureus was not diminished. The S. aureus-induced respiratory burst and neutrophil extracellular trap release from PMNs also remained uninhibited by CF sputum. In summary, our data demonstrate that the CF airway environment limits killing of S. aureus by PMNs and provides a new in vitro experimental model to study this phenomenon and its mechanism.

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Preliminary Report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 Infection (Preprint)

10.2196/preprints.20200 ◽

2020 ◽

Author(s):

Hacer Kuzu Okur ◽

Koray Yalcin ◽

Cihan Tastan ◽

Sevda Demir ◽

Bulut Yurtsever ◽

...

Keyword(s):

Cystic Fibrosis ◽

Respiratory Tract ◽

Mononuclear Cells ◽

Multiple Organ ◽

Peripheral Blood Mononuclear ◽

Dornase Alfa ◽

Tract Infections ◽

Adult Peripheral Blood

UNSTRUCTURED Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with dornase alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that dornase alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

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Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22052530 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2530

Author(s):

Bijean D. Ford ◽

Diego Moncada Giraldo ◽

Camilla Margaroli ◽

Vincent D. Giacalone ◽

Milton R. Brown ◽

...

Keyword(s):

Cystic Fibrosis ◽

Bactericidal Activity ◽

Scavenger Receptor ◽

Receptor Expression ◽

Blood Monocytes ◽

Bacterial Killing ◽

Blood Neutrophils ◽

Vitro Model

Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection.

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Prognosis and treatment of 46 Chinese pediatric cystic fibrosis patients

BMC Pediatrics ◽

10.1186/s12887-021-02789-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qionghua Chen ◽

Yuelin Shen ◽

Hui Xu ◽

Xiaolei Tang ◽

Haiming Yang ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Respiratory Tract Infections ◽

Adverse Reactions ◽

Clinical Presentation ◽

Public Awareness ◽

Sputum Production ◽

Tract Infections ◽

Lost To Follow Up

Abstract Background Since public awareness of cystic fibrosis (CF) has increased, more children have been diagnosed with CF in China. This study aimed to investigate medical and other challenges faced by pediatric CF patients in China. Method Treatments and treatment outcomes were retrospectively analyzed for 46 pediatric CF patients diagnosed from August 2009 to June 2019. Pre- and post-treatment results were compared using independent samples t-test. Results Of 46 pediatric CF study patients, four died and five were lost to follow-up. Thirty-seven patients were monitored for 0.03 to 9.21 years; patients exhibited fewer attacks of respiratory tract infections after diagnosis (4.49 ± 2.13 episodes/year before diagnosis vs 1.97 ± 1.87 times/year after 1-year treatment, p < 0.05), significantly reduced sputum production and experienced 1.62 ± 1.71 exacerbations/year. Patient mean body mass index was 16.87 ± 3.53 and pancreatic malfunction persisted in 15 patients. For 17 children, no significant differences in lung function were found at follow-up as compared to lung function at diagnosis (FEV1: 82.45% ± 16.56% vs 75.26% ± 22.34%, FVC: 87.18% ± 13.64% vs 86.99% ± 19.95%, FEF75%: 46.51% ± 28.78% vs 36.63% ± 24.30%, P = 0.27, 0.97, 0.20, respectively). Pseudomonas aeruginosa (17/27) and bronchiectasis (22/22) were found during follow-up evaluation. Twenty-four patients (64.8%) maintained good adherence to therapies. Overall, azithromycin and tobramycin treatments were administered for 0.5–62 months and 0.5–48 months, respectively, and triggered no obvious adverse reactions. Conclusion No obvious declines in clinical presentation or lung function were found in Chinese pediatric CF patients after receiving standard therapeutic and active treatments, although malnutrition and low compliance were persistent challenges.

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Pseudomonas aeruginosa uses multiple receptors for adherence to laminin during infection of the respiratory tract and skin wounds

Scientific Reports ◽

10.1038/s41598-019-54622-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Magnus Paulsson ◽

Yu-Ching Su ◽

Tamara Ringwood ◽

Fabian Uddén ◽

Kristian Riesbeck

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Outer Membrane ◽

Heparin Binding ◽

Surface Receptors ◽

Binding Domains ◽

Laminin Receptors ◽

Multiple Receptors ◽

Main Component ◽

Tract Infections

AbstractPseudomonas aeruginosa efficiently adheres to human tissues, including the lungs and skin, causing infections that are difficult to treat. Laminin is a main component of the extracellular matrix, and in this study we defined bacterial laminin receptors on P. aeruginosa. Persistent clinical P. aeruginosa isolates from patients with cystic fibrosis, wounds or catheter-related urinary tract infections bound more laminin compared to blood isolates. Laminin receptors in the outer membrane were revealed by 2D-immunblotting, and the specificities of interactions were confirmed with ELISA and biolayer interferometry. Four new high-affinity laminin receptors were identified in the outer membrane; EstA, OprD, OprG and PA3923. Mutated bacteria devoid of these receptors adhered poorly to immobilized laminin. All bacterial receptors bound to the heparin-binding domains on LG4 and LG5 of the laminin alpha chain as assessed with truncated laminin fragments, transmission electron microscopy and inhibition by heparin. In conclusion, P. aeruginosa binds laminin via multiple surface receptors, and isolates from lungs of cystic fibrosis patients bound significantly more laminin compared to bacteria isolated from the skin and urine. Since laminin is abundant in both the lungs and skin, we suggest that laminin binding is an important mechanism in P. aeruginosa pathogenesis.

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Urinary Excretion and Bactericidal Activities of a Single Oral Dose of 400 Milligrams of Fleroxacin versus a Single Oral Dose of 800 Milligrams of Pefloxacin in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.7.1659 ◽

1998 ◽

Vol 42 (7) ◽

pp. 1659-1665 ◽

Cited By ~ 15

Author(s):

Kurt G. Naber ◽

Ursula Theuretzbacher ◽

Martina Kinzig ◽

Orlin Savov ◽

Fritz Sörgel

Keyword(s):

Oral Dose ◽

Healthy Volunteers ◽

Single Oral Dose ◽

E Coli ◽

Wide Range ◽

The Mean ◽

Bactericidal Activities ◽

Tract Infections ◽

Time Kill ◽

Randomized Crossover Study

ABSTRACT Twelve healthy volunteers participated in this randomized crossover study to compare the concentrations and recovery levels of fleroxacin and pefloxacin in urine and to assess their bactericidal activities against 12 strains of urinary pathogens with different susceptibilities over a wide range of MICs. The volunteers received a single oral dose of 400 mg of fleroxacin or 800 mg of pefloxacin. The mean cumulative renal excretion of unchanged fleroxacin,N-demethyl-fleroxacin, and N-oxide-fleroxacin accounted for 67, 7, and 6% of the total dose, respectively. The total urinary recovery of pefloxacin and the active metabolite norfloxacin was 34%. In the time-kill and the urinary bactericidal titer (UBT) studies, only the subjects’ urine not supplemented with broth was used. With most tested organisms and both quinolones it took more than 8 h to achieve a reduction in CFU of 99.9% (3 log units). Overall, there was a good correlation between UBTs and MICs for the strains. Against Escherichia coli ATCC 25922 the median UBTs were similar for both antibiotics and at least 1:8 for 96 h; against the E. coli strain for which the MIC was 0.5 μg/ml the UBT was at least 1:4 for 48 h. The UBTs of both drugs against Klebsiella pneumoniae were at least 1:16 for 72 h. The UBTs for Staphylococcus aureus (the MIC for which was 16 μg/ml) of both antibiotics were low, and in some of the samples, no bactericidal titers were observed. UBTs for Proteus mirabilis of pefloxacin are significantly higher than those of fleroxacin. For Pseudomonas aeruginosa the median UBTs were present for the 24-to-48-h interval. The same is true forEnterococcus faecalis. Against Staphylococcus saprophyticus, UBTs were present for at least 48 h with both quinolones. Overall, a single oral dose of 400 mg of fleroxacin exhibits UBTs comparable to those of 800 mg of pefloxacin. Therefore, it may be expected that half of the dose of fleroxacin gives comparable results in the treatment of urinary tract infections; this should be substantiated in comparative clinical trials.

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Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01150-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 9

Author(s):

Vanessa E. Rees ◽

Rajbharan Yadav ◽

Kate E. Rogers ◽

Jürgen B. Bulitta ◽

Veronika Wirth ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Time Course ◽

Respiratory Infections ◽

Resistant Bacteria ◽

Infection Model ◽

Time Curve ◽

Bacterial Killing ◽

Content Type ◽

Concentration Time

ABSTRACT Hypermutable Pseudomonas aeruginosa organisms are prevalent in chronic respiratory infections and have been associated with reduced lung function in cystic fibrosis (CF); these isolates can become resistant to all antibiotics in monotherapy. This study aimed to evaluate the time course of bacterial killing and resistance of meropenem and ciprofloxacin in combination against hypermutable and nonhypermutable P. aeruginosa. Static concentration time-kill experiments over 72 h assessed meropenem and ciprofloxacin in mono- and combination therapies against PAO1 (nonhypermutable), PAOΔmutS (hypermutable), and hypermutable isolates CW8, CW35, and CW44 obtained from CF patients with chronic respiratory infections. Meropenem (1 or 2 g every 8 h [q8h] as 3-h infusions and 3 g/day as a continuous infusion) and ciprofloxacin (400 mg q8h as 1-h infusions) in monotherapies and combinations were further evaluated in an 8-day hollow-fiber infection model study (HFIM) against CW44. Concentration-time profiles in lung epithelial lining fluid reflecting the pharmacokinetics in CF patients were simulated and counts of total and resistant bacteria determined. All data were analyzed by mechanism-based modeling (MBM). In the HFIM, all monotherapies resulted in rapid regrowth with resistance at 48 h. The maximum daily doses of 6 g meropenem (T>MIC of 80% to 88%) and 1.2 g ciprofloxacin (area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC], 176), both given intermittently, in monotherapy failed to suppress regrowth and resulted in substantial emergence of resistance (≥7.6 log10 CFU/ml resistant populations). The combination of these regimens achieved synergistic killing and suppressed resistance. MBM with subpopulation and mechanistic synergy yielded unbiased and precise curve fits. Thus, the combination of 6 g/day meropenem plus ciprofloxacin holds promise for future clinical evaluation against infections by susceptible hypermutable P. aeruginosa.

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Dysregulation of prostaglandins, leukotrienes and lipoxin A4 in bronchiectasis

Thorax ◽

10.1136/thoraxjnl-2020-216475 ◽

2021 ◽

pp. thoraxjnl-2020-216475

Author(s):

Pallavi Bedi ◽

Kerstin Ziegler ◽

Phil D Whitfield ◽

Donald Davidson ◽

Adriano Giorgio Rossi ◽

...

Keyword(s):

Healthy Volunteers ◽

Severe Disease ◽

Stable State ◽

Lavage Fluid ◽

Forced Expiratory Volume ◽

Lipid Mediators ◽

Prostaglandin E ◽

Lipoxin A4 ◽

Bacterial Killing ◽

Anti Inflammatory

IntroductionBronchiectasis is characterised by excessive neutrophilic inflammation. Lipid mediators such as prostaglandins and leukotrienes have crucial roles in the inflammatory response. Further characterisation of these lipids and understanding the interplay of anti-inflammatory and proinflammatory lipid mediators could lead to the development of novel anti-inflammatory therapies for bronchiectasis.AimThe aim of our study was to characterise the lipids obtained from serum and airways in patients with bronchiectasis in the stable state.MethodsSix healthy volunteers, 10 patients with mild bronchiectasis, 15 with moderate bronchiectasis and 9 with severe bronchiectasis were recruited. All participants had 60 mL of blood taken and underwent a bronchoscopy while in the stable state. Lipidomics was done on serum and bronchoalveolar lavage fluid (BALF).ResultsIn the stable state, in serum there were significantly higher levels of prostaglandin E2 (PGE2), 15-hydroxyeicosatetranoic acid (15-HETE) and leukotriene B4 (LTB4) in patients with moderate–severe disease compared with healthy volunteers. There was a significantly lower level of lipoxin A4 (LXA4) in severe bronchiectasis.In BALF, there were significantly higher levels of PGE2, 5-HETE, 15-HETE, 9-hydroxyoctadecadienoic acid and LTB4 in moderate–severe patients compared with healthy volunteers.In the stable state, there was a negative correlation of PGE2 and LTB4 with % predicted forced expiratory volume in 1 s and a positive correlation with antibiotic courses.LXA4 improved blood and airway neutrophil phagocytosis and bacterial killing in patients with bronchiectasis. Additionally LXA4 reduced neutrophil activation and degranulation.ConclusionThere is a dysregulation of lipid mediators in bronchiectasis with excess proinflammatory lipids. LXA4 improves the function of reprogrammed neutrophils. The therapeutic efficacy of LXA4 in bronchiectasis warrants further studies.

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