Factors influencing the acquisition and eradication of early Pseudomonas aeruginosa infection in cystic fibrosis

In recent years considerable improvements have been made in increasing the life expectancy of patients with cystic fibrosis. New highly effective modulator therapies targeting the underlying defect in the cystic fibrosis transmembrane conductance regulator protein are expected to enhance lifespan even further. However, chronic Pseudomonas aeruginosa pulmonary infections continue to threaten CF patient lung health and mortality rates. Early and aggressive antibiotic eradication therapies targeting P. aeruginosa are standard practice, but these eradication therapies fail in 10–40% of patients. The reasons for P. aeruginosa eradication failure remain unclear. Thus, this review summarizes the evidence to date for pseudomonal acquisition and eradication failure in the cystic fibrosis lung. A complex combination of host and bacterial factors are responsible for initial establishment of P. aeruginosa pulmonary infections. Moreover, host and pseudomonal factors, polymicrobial interactions, and antimicrobial limitations in relation to P. aeruginosa eradication therapy failure are summarized.     

Early Pseudomonas aeruginosa predicts poorer pulmonary function in preschool children with cystic fibrosis

BackgroundWe previously reported relatively normal pulmonary function (2 years of age) and computed tomography (CT, 1 year of age) in cystic fibrosis (CF) newborn screened (NBS) infants. We now report follow up of these children to preschool age.Methods67 NBS children with CF and 41 healthy controls underwent pulmonary function tests in infancy (～3 months, 1 year and 2 years) and at preschool (3–6 years). Broncho-alveolar lavage (BAL) and CT were undertaken in those with CF at 1 year. Primary outcomes at preschool were lung clearance index (LCI) and forced expired volume (FEV_0.75). Risk factors for lung function impairment were identified by regression modelling, emphasising factors that could be identified or measured in the first 2 years of life.ResultsAt preschool age children with CF had poorer lung function than controls, mean(95% CI) difference in LCI z-score: 1.47(0.96;1.97) and FEV_0.75 z-score -0.54(-0.98; -0.10). Isolation of Pseudomonas aeruginosa before 6 months was a highly significant predictor of raised (abnormal) preschool LCI, associated with a mean (95%CI) increase of 1.69(0.43, 2.95) z-scores, compared to those with no Pseudomonas aeruginosa during the first 2 years of life. Including 2 year LCI and 1 year CT data in the predictive model increased the r² from 13% to 61%.ConclusionsLung function deteriorates after 2 years in NBS children with CF. Isolation of Pseudomonas aeruginosa before 6 months and minor abnormalities of infant lung function tests and CT in infancy are associated with higher preschool LCI.     

Early detection using qPCR of Pseudomonas aeruginosa infection in children with cystic fibrosis undergoing eradication treatment

Background

Infection with Pseudomonas aeruginosa (Pa) with a chronic phenotype is associated with antibiotic eradication therapy (AET) failure. Our objective was to determine whether higher levels of Pa (detected using qPCR) prior to culture positivity were associated with AET failure in pediatric CF patients.

Extrapulmonary sites of Pseudomonas aeruginosa in adults with cystic fibrosis.

BACKGROUND: Pseudomonas aeruginosa infection is seldom eradicated in patients with cystic fibrosis despite intensive antipseudomonal treatment. Upper airway sites of infection may contribute to perpetuation of lower airways infection. This study was designed to find out which extrapulmonary sites are infected and whether the strains at these sites are identical to those in the lungs. METHODS: Sputum and upper airway samples from 42 patients were cultured for P aeruginosa and stool samples from 20 patients were also tested. Nineteen isolates from sputum and extrapulmonary sites from four patients were genotyped with the pCM tox probe. RESULTS: P aeruginosa was isolated from the sputum of 36 patients, 34 of whom had infection in the upper airways. Six of the 20 patients tested were positive for P aeruginosa in the stool. The nasopharynx was colonised in 30 patients, the oropharynx in 29, the middle meatus in 13, the external nares in six, and the inferior turbinate in four. Three of four patients tested had the same strain of P aeruginosa (a different one in each individual) in the sputum and the upper airways, and in two of the three the stool isolate was a different strain. CONCLUSION: Most adults with cystic fibrosis and P aeruginosa pulmonary infection have upper airway reservoirs of the organism and strains from these sites are identical to those in the lungs.     

Mucoid Pseudomonas aeruginosa and regional inflammation in the cystic fibrosis lung

BackgroundPseudomonas aeruginosa is the prominent bacterial pathogen in the cystic fibrosis (CF) lung and contributes to significant morbidity and mortality. Though P. aeruginosa strains initially colonizing the CF lung have a nonmucoid colony morphology, they often mutate into mucoid variants that are associated with clinical deterioration. Both nonmucoid and mucoid P. aeruginosa variants are often co-isolated on microbiological cultures of sputum collected from CF patients. With regional variation in bronchiectasis, tissue damage, inflammation, and microbial colonization, lobar distribution of nonmucoid and mucoid P. aeruginosa variants may impact local microenvironments in the CF lung, but this has not been well-studied.MethodsWe prospectively collected lobe-specific bronchoalveolar lavage (BAL) fluid from a CF patient cohort (n = 14) using a standardized bronchoscopic protocol where collection was performed in 6 lobar regions. The lobar BAL specimens were plated on P. aeruginosa-selective media and proinflammatory cytokines (IL-1, TNF, IL-6 and IL-8) were measured via cytokine array. Correlations between infecting P. aeruginosa variants (nonmucoid, mucoid, or mixed-variant populations), the lobar regions in which these variants were found, and regional proinflammatory cytokine concentrations were measured.ResultsP. aeruginosa mucoid and nonmucoid variants were homogenously distributed throughout the CF lung. However, infection with mucoid variants (found within single- or mixed-variant populations) was associated with significantly greater regional inflammation. The upper and lower lobes of the CF lung did not exhibit differences in inflammatory cytokine concentrations.ConclusionsMucoid P. aeruginosa infection is a microbial determinant of regional inflammation within the CF lung.     

Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis.

BACKGROUND: Increasing resistance to standard antibiotics has been demonstrated in CF patients colonised by Pseudomonas aeruginosa. The antibiotic Fosfomycin has a unique mode of action against this organism, and may protect against aminoglycoside mediated renal and ototoxic effects. However, there is little published experience of this drug in IV form, and it is not licensed for use in the UK. METHODS: In combination with other antibiotics, we used Fosfomycin to treat 30 pulmonary exacerbations in 15 adult CF patients colonised by P. aeruginosa, mainly multiresistant strains. All patients gave informed consent. We cultured sputum prior to treatment and measured spirometry, renal function, and symptoms before and after treatment, and recorded any side effects. RESULTS: One patient developed nausea and Fosfomycin treatment was withdrawn. The remaining patients showed clinical resolution of their chest exacerbations (mean FEV1% predicted: pre 41.1 vs. post 49.4, P<0.001). Although there was a statistical increase in plasma urea (pre 3.9 mmol/l vs. post 4.3, P<0.03), this was still within the normal range. Plasma creatinine was unchanged. CONCLUSIONS: This study shows that IV Fosfomycin is well tolerated by adult patients with CF and can be useful in the treatment of those colonised with multiresistant P. aeruginosa.     

Multiple antibiotic-resistant Pseudomonas aeruginosa and lung function decline in patients with cystic fibrosis

BackgroundThe goal of this study was to determine the association of multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) acquisition with lung function decline in patients with cystic fibrosis (CF).MethodsUsing data from Epidemiologic Study of Cystic Fibrosis (ESCF), we identified patients with spirometry data and MARPA, defined as PA (1) resistant to gentamicin and either tobramycin or amikacin, and (2) resistant to ≥ 1 antipseudomonal beta lactam. MARPA had to be detected in a respiratory culture after ≥ 2 years of PA-positive but MARPA-negative respiratory cultures. Multivariable piecewise linear regression was performed to model the annual rate of decline in forced expiratory volume in 1 second (FEV₁) % predicted 2 calendar years before and after the index year of MARPA detection, adjusting for patient characteristics and CF therapies.ResultsIn total, 4349 patients with chronic PA and adequate PFT data were identified; 1111 subsequently developed MARPA, while 3238 patients were PA positive but MARPA negative. Compared with patients who did not acquire MARPA, MARPA-positive patients had lower FEV₁ and received more oral (p < 0.013) and inhaled (p < 0.001) antibiotic therapy. Mean FEV₁ decline did not change significantly after MARPA detection (− 2.22% predicted/year before detection and − 2.43 after, p = 0.45). There was no relationship between persistent infection or FEV₁ quartile and FEV₁ decline.ConclusionsNewly detected MARPA was not associated with a significant change in the rate of FEV₁ decline. These results suggest that MARPA is more likely to be a marker of more severe disease and more intensive therapy, and less likely to be contributing independently to more rapid lung function decline.     

Role of alginate in infection with mucoid Pseudomonas aeruginosa in cystic fibrosis.

BACKGROUND: Chronic bronchopulmonary infection with mucoid, alginate producing Pseudomonas aeruginosa occurs characteristically in patients with cystic fibrosis. Alginate may be a virulence factor for P aeruginosa infection in such patients. METHODS: Forced vital capacity (FVC), nutritional state and the antibody response to P aeruginosa were determined at regular intervals from three years before chronic P aeruginosa infection to 10 years afterwards in 73 patients with cystic fibrosis. All patients were treated intensively with antipseudomonal chemotherapy during the study period. RESULTS: FVC was reduced in all patients who subsequently developed P aeruginosa infection before they acquired the infection, indicating significant pre-existing lung damage when compared with patients who remained free of P aeruginosa. Lung function and nutritional state remained unchanged after 10 years of infection, except in the patients who died of P aeruginosa lung infection. The FVC and height and weight of patients infected with nonmucoid strains of P aeruginosa were similar to those of uninfected patients. Patients infected with mucoid strains had poorer lung function and nutritional state for the first five years after infection compared with patients with nonmucoid strains. Such infection was also associated with greater IgG and IgA antibody responses to P aeruginosa standard antigen compared with nonmucoid infection. Concentrations of antibody to alginate were similar in patients with non-mucoid and mucoid infection. Noticeably increased concentrations of IgA antibodies to P aeruginosa standard antigen were observed early after the onset of infection in patients who subsequently died. CONCLUSION: Alginate producing P aeruginosa infection is associated with a hyperimmune response and poor clinical condition, suggesting that alginate production is a virulence factor in such infections in patients with cystic fibrosis.     

Effectiveness of inhaled tobramycin in eradicating Pseudomonas aeruginosa in children with cystic fibrosis

BackgroundInhaled tobramycin therapy has been shown to be efficacious in clinical trials for the eradication of initial Pseudomonas aeruginosa infection in children with cystic fibrosis (CF). However, the effectiveness of different regimens in eradicating P. aeruginosa and preventing the development of chronic infection in actual clinical settings has yet to be determined.MethodsThis was an observational study of children (< 18 years of age) with CF with incident P. aeruginosa infection from 2005–2012 based on data collected from the Toronto CF Database and medical charts. Patients who received inhaled tobramycin (80 mg/2 ml twice daily for 365 days) were compared to those who received tobramycin inhalation solution (TIS) (300 mg/5 ml twice daily for 28 days) with respect to eradication and development of chronic infection. We also examined the risk factors for recurrence of infection.ResultsDuring the study period, 65 patients were identified with incident P. aeruginosa, of which 7 (11%) failed eradication therapy. Eradication failure was similar between the two treatment groups. A total of 4 patients (6%) developed chronic P. aeruginosa infection in the 12 months following the end of therapy with no differences between treatment groups. Female gender, older age, pancreatic insufficiency, lower lung function and worse nutritional status were identified as risk factors for recurrence of P. aeruginosa infection.ConclusionsBoth regimens of inhaled tobramycin have similar effectiveness in eradicating P. aeruginosa and preventing chronic P. aeruginosa infection in CF patients in clinical practice. Further work is needed, however, to identify patient characteristics and bacterial factors that play a role in eradication failure, in order to develop more effective antimicrobial rescue treatment strategies.     

Effectiveness of a stepwise Pseudomonas aeruginosa eradication protocol in children with cystic fibrosis

Introduction

Antibiotic eradication therapy (AET) for initial Pseudomonas aeruginosa (Pa) infection is standard of care in children with cystic fibrosis (CF), but information is limited on treatment for patients who fail initial AET. The aim of this study was to evaluate the effectiveness of a multi-step protocol for AET for new-onset Pa infections in children with CF.

Predicting risk-adjusted incidence rates of methicillin-resistant Staphylococcus Aureus and Pseudomonas Aeruginosa in cystic fibrosis programs in the United States

BackgroundHealthcare-associated transmission of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa occurs for people with cystic fibrosis (CF), but CF programs lack a process to monitor incidence rates (IRs). We assessed predictors of incident infections and created a model to determine risk-adjusted IRs for CF programs.MethodsUsing the CF Foundation Patient Registry data for all patients from 2012 to 2015, coefficients for variables that predicted IRs were estimated. Hazard functions were then used to predict IRs of MRSA and P. aeruginosa for CF programs based on their patient and program characteristics. Predicted IRs were compared with observed IRs over multiple time intervals.ResultsMultiple patient and program characteristics were identified as predictors of observed IRs. Our model's predicted IRs closely aligned with observed IRs for most CF programs. Alarm values (defined as observed IR > 95% confidence interval of predicted IR) were found at 5.9%, 5.9%, 6.0% (adult, pediatric, affiliate) of programs for MRSA and 3.0%, 1.7%, 0.0% (adult, pediatric, affiliate) of programs for P. aeruginosa.ConclusionsWe found patient and program characteristics that predicted MRSA and P. aeruginosa IRs. Our model accurately predicted risk-adjusted IRs of MRSA and P. aeruginosa. CF programs could use our model to monitor their IRs and potentially improve infection prevention and control.     

Aminoglycoside therapy against Pseudomonas aeruginosa in cystic fibrosis: A review

In patients with cystic fibrosis (CF), respiratory infections with the opportunistic bacterial pathogen Pseudomonas aeruginosa have a major impact on morbidity and mortality. Aminoglycosides, especially tobramycin, have been used successfully to combat these infections. Aminoglycoside penetration of bronchial secretions is poor when the antibiotic is administered intravenously. Nebulization allows direct delivery of the drug to the sites of infection within the airways, while avoiding systemic exposure. Published clinical data show that inhaled tobramycin reduces the bacterial load, improves lung function and reduces the number of hospital admissions. Inhaled tobramycin has been used successfully to eradicate P. aeruginosa in patients with early infection. Maintaining clinical benefits requires chronic tobramycin treatment, and the concept of chronic intermittent inhaled treatment (typically, alternating drug and drug-free periods of 28 days) was introduced to minimize the emergence of aminoglycoside resistant P. aeruginosa strains. Other therapeutic advances include the development of different tobramycin formulations and nebulizers that reduce delivery time without compromising efficacy. An optimal treatment regimen for patients with CF with early or intermittent P. aeruginosa infections remains a high priority to maintain long-term lung health.     

Emergence and impact of oprD mutations in Pseudomonas aeruginosa strains in cystic fibrosis

BackgroundAntimicrobial resistance in cystic fibrosis (CF) Pseudomonas aeruginosa airway infection is complex and often attributed to chromosomal mutations. How these mutations emerge in specific strains or whether particular gene mutations are clinically informative is unclear. This study focused on oprD, which encodes an outer membrane porin associated with carbapenem resistance when it is downregulated or inactivated.AimDetermine how mutations in oprD emerge in two prevalent Australian shared CF strains of P. aeruginosa and their clinical relevance.MethodsThe two most common shared CF strains in Queensland were investigated using whole genome sequencing and their oprD sequences and antimicrobial resistance phenotypes were established. P. aeruginosa mutants with the most common oprD variants were constructed and characterised. Clinical variables were compared between people with or without evidence of infection with strains harbouring these variants.ResultsFrequently found nonsense mutations arising from a 1-base pair substitution in oprD evolved independently in three sub-lineages, and are likely major contributors to the reduced carbapenem susceptibility observed in the clinical isolates. Lower baseline FEV₁ %predicted was identified as a risk factor for infection with a sub-lineage (odds ratio=0.97; 95% confidence interval 0.96-0.99; p<0.001). However, acquiring these sub-lineage strains did not confer an accelerated decline in FEV₁ nor increase the risk of death/lung transplantation.ConclusionsSub-lineages harbouring specific mutations in oprD have emerged and persisted in the shared strain populations. Infection with the sub-lineages was more likely in people with lower lung function, but this was not predictive of a worse clinical trajectory.