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AeroVanc – MRSA and Cystic Fibrosis

Pharmacokinetics of Vancomycin in Plasma and Sputum Following Pulmonary Administration in Cystic Fibrosis Patients with Persistent Methicillin-Resistant Staphylococcus Aureus Infection were presented at the 2016 North America Cystic Fibrosis Conference in October 2016.

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Inhaled antibiotics dramatically improve targeting of drug to the site of respiratory infections, while simultaneously
minimizing systemic exposure and associated toxicity. The high local concentrations of antibiotic may
enable more effective treatment of multi-drug resistant pathogens. This review explores barriers to effective
treatment with inhaled antibiotics. In addition, potential opportunities for improvements in treatment are
reviewed.

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Background
Monitoring potential changes in the epidemiology of cystic fibrosis (CF) pathogens furthers our understanding of the potential impact of interventions.

Methods
We performed a retrospective analysis using data reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) from 2006 to 2012 to determine the annual percent changes in the prevalence and incidence of selected CF pathogens. Pathogens included Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S aureus (MRSA), Haemophilus influenzae, Burkholderia cepacia complex, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans. Changes in nontuberculous mycobacteria (NTM) prevalence were assessed from 2010 to 2012, when the CFFPR collected NTM species.

Results
In 2012, the pathogens of highest prevalence and incidence were MSSA and P aeruginosa, followed by MRSA. The prevalence of A xylosoxidans and B cepacia complex were relatively low. From 2006 to 2012, the annual percent change in overall (as well as in most age strata) prevalence and incidence significantly decreased for P aeruginosa and B cepacia complex, but significantly increased for MRSA. From 2010 to 2012, the annual percent change in overall prevalence of NTM and Mycobaterium avium complex increased.

Conclusion
The epidemiology of CF pathogens continues to change. The causes of these observations are most likely multifactorial and include improvements in clinical care and infection prevention and control. Data from this study will be useful to evaluate the impact of new therapies on CF microbiology.

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Report from the 27th annual North American CF (NACF) conference, Salt Lake City, UT, October 17-19, 2013 – Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a clinically significant pathogen and there is a growing recognition of the need to treat persistent MRSA infection to improve outcomes in CF patients…

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Background
Risk factors for methicillin-resistant Staphylococcus aureus (MRSA) in Cystic Fibrosis (CF) and the impact on CF disease progression are still under debate.
The objectives of this study were to determine clinical variables associated with MRSA colonization and examine impact on FEV1 evolution in CF patients.

Methods
A retrospective case–control study using the University Hospital of Brussels CF clinic patient registry from 2002 to 2010, comparing clinical variables and decline of FEV1 of MRSA positive patients with age and sex matched controls, chronically colonized with S. aureus.

Results
Thirty of the 165 CF patients, chronically colonized with S. aureus, had cultures positive for MRSA (18.2%). Excluding patients under 4 years, the prevalence became 15.2% (23/151). Chronic colonization (i.e., three or more consecutive positive cultures) was found in 19/151 (12.6%). The MRSA positive group showed a higher proportion of patients with genotype F508del, less pancreas sufficient patients, more bronchiectasis and more frequent hospitalization.

The FEV1 recorded one year prior to, and at the moment of MRSA acquisition, was lower but not significantly different from that obtained in controls (72.9% ± 26.6 vs 84.3 ± 21.8 and 68.2% ± 27.1 vs 81.4% ± 24.3 respectively, pN0.1). However, FEV1 decline over 2- and 6-year periods, were significantly greater in the chronic MRSA group than in the controls (−5% ± 5.5 vs −2.5 ± 2.3 over 2 years (p = 0.043) and −1.8% ± 4.6 vs −1.0% ± 1.9 over a 6-year period (p = 0.026)).

Conclusion
In our center the prevalence of MRSA in CF patients, chronically colonized with S. aureus and over the age of 4 years, was 15.2%
(12.6% chronic infection). MRSA colonization was shown to be associated with a genotype F508del, presence of bronchiectasis and hospitalization. Our spirometric data also show that a MRSA episode entails an FEV1 decline that is almost double that predicted for CF patients who can remain unaffected by MRSA.

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The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the respiratory tract of individuals with cystic fibrosis (CF) has increased dramatically; however, its impact on outcomes in CF is unclear. Because the time between infection with bacteria in CF and death can be decades, observational studies with long periods of follow-up are well suited to address the current gap in knowledge…

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Rationale
Patients with cystic fibrosis periodically experience pulmonary exacerbations. Previous studies have noted that some patients’ lung function (FEV1) does not improve with treatment.

Objectives
To determine the proportion of patients treated for a pulmonary exacerbation that does not recover to spirometric baseline, and to identify factors associated with the failure to recover to spirometric baseline.

Methods
Cohort study using the Cystic Fibrosis Foundation Patient Registry from 2003–2006. We randomly selected one pulmonary
exacerbation treated with intravenous antibiotics per patient and compared the best FEV1 in the 3 months after treatment with the best FEV1 in the 6 months before treatment. Recovery to baseline was defined as any FEV1 in the 3 months after treatment that was greater than or equal to 90% of the baseline FEV1. Multivariable logistic regression was used to estimate associations with the failure to recover to baseline FEV1.

Measurements and Main Results
Of 8,479 pulmonary exacerbations, 25% failed to recover to baseline FEV1. A higher risk of failing to recover to baseline was associated with female sex; pancreatic insufficiency; being undernourished; Medicaid insurance; persistent infection with Pseudomonas aeruginosa, Burkholderia cepacia complex, or methicillin-resistant Staphylococcus aureus; allergic bronchopulmonary aspergillosis; a longer time since baseline spirometric assessment; and a larger drop in FEV1 from baseline to treatment initiation.

Conclusions
For a randomly selected pulmonary exacerbation, 25% of patients’ pulmonary function did not recover to baseline after treatment
with intravenous antibiotics. We identified factors associated with the failure to recover to baseline, allowing clinicians to identify patientswhomay benefit from closermonitoring andmore aggressive treatment.

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Rationale
The prevalence in cystic fibrosis (CF) of respiratory cultures with methicillin-resistant Staphylococcus aureus (MRSA) has dramatically increased over the last 10 years, but the effect of MRSA on FEV1 decline in CF is unknown.

Objectives
To determine the association between MRSA respiratory infection and FEV1 decline in children and adults with CF.

Methods
This was a 10-year cohort study using the Cystic Fibrosis Foundation patient registry from 1996–2005. We studied individuals who developed new MRSA respiratory tract infection. Repeated-measures regression was used to assess the association between MRSA and FEV1 decline, adjusted for confounders, in individuals aged 8–21 years and adults (aged 22–45 yr). Two different statistical models were used to assess robustness of results.

Measurements and Main Results
The study cohort included 17,357 patients with an average follow-up of 5.3 years. During the study period, 1,732 individuals developed new persistent MRSA infection (≥3 MRSA cultures; average, 6.8 positive cultures) and were subsequently followed for an average of 3.5 years. Even after adjustment for confounders, rate of FEV1 decline in individuals aged 8–21 years with persistent MRSA was more rapid in both statistical models. Their average FEV1 decline of 2.06% predicted/year was 43% more rapid than the 1.44% predicted/year in those without MRSA (difference, −0.62% predicted/yr; 95% confidence interval, −0.70 to −0.54; P < 0.001). Effect of MRSA on FEV1 decline in adults was not clinically significant.

Conclusions
Persistent infection with MRSA in individuals with CF between the ages of 8 and 21 years is associated with a more rapid rate of decline in lung function.

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Molgradex – GM-CSF and PAP

Results of Savara’s (formerly Serendex) phase I clinical trial for molgramostim were presented at the ATS (American Thoracic Society) congress in May 2016.

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Background
Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and effi cacious in several reports. However, some reports of subcutaneous injection described transient benefi t in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.

Methods
To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the fi ndings of 30-month observation after the end of inhalation therapy.

Results
During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no signifi cant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment ( P , .01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A signifi cant difference in the time to additional treatment between the high %VC group (%VC 80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test ( P , .0005).

Conclusions
These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence.

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Background
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare pulmonary disease caused by functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF). Administration of GM-CSF represents a potential therapeutic strategy in management of aPAP. Herein, we systematically review the efficacy of GM-CSF therapy in aPAP.

Methods
We searched the PubMed and EmBase databases for studies reporting the use of GM-CSF in aPAP. We calculated the proportion with 95% Cl to assess the response and relapse rates of GM-CSF therapy in individual studies and pooled them using a random-effects model. Statistical heterogeneity was assessed using the 12 and Cocbran Q tests. Puhlication bias was analyzed using funnel plot and Egger and Begg-Mazumdar tests.

Results
Our initial searches yielded 1,585 studies. Of tbese, five observational studies (involving 94 patients) were included for analysis. Three studies used the suhcutaneous route, and two studies used the inhalational route for GM-CSF administration. The response rate of GM-CSF varied from 43% to 92%, with tbe pooled response rate heing 58.6% (95% Cl, 42.7-72.9). The relapse rate in GM-CSF responders was 29. 7% (95% Cl, 10.5-60.4). Tbere was no evidence of statistical heterogeneity or publication bias for the outcome of response. GM-CSF therapy was associated ,vith minor complications, sucb as fever and local complications at the sile of administration.

Conclusions
GM-CSF represents a useful approach in the treatment of aPAP. The optimal indi­cation, dose and duration of therapy, and the factors predicting response and relapse need to be deflned by future studies.

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Rationale
Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.

Objectives
To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.

Methods
We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk).

Measurements and Main Results
Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year.

Conclusions
Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).

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Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) auto-antibodies have been found in many patients with pulmonary alveolar proteinosis (PAP). The present study reports a retrospective case series of patients who used aerosolised GM-CSF in the treatment of idiopathic PAP. Between 1999 and 2003, 12 patients elected to receive aerosolised GM-CSF (250 microg b.i.d. every other week) in lieu of whole-lung lavage or observation. Patient characteristics, pulmonary function tests, arterial blood gas analysis, laboratory values and chest radiographs were extracted from the patient’s medical records. Of the six patients tested, all had GM-CSF neutralising antibodies. Additionally, abnormalities in GM-CSF gene expression (one patient), receptor expression (two patients) and ability to upregulate adhesion molecules (one patient) were found. All patients except one had a positive response (mean improvements in arterial oxygen tension, alveolar-arterial oxygen gradient, carbon monoxide diffusing capacity of the lung and forced vital capacity were 17.1 mmHg, 18.4 mmHg, 16.6% pred and 13.5% pred, respectively). Two patients made a complete recovery and were disease free 1 and 2 yrs after discontinuing treatment. Four patients showed complete response to both the initial course or when treated again for recurrence after discontinuation of treatment. One patient required dose escalation (500 microg b.i.d.) with complete response. GM-CSF was well tolerated without late toxicity after median (range) follow-up of 30.5 (3-68) months. In conclusion, aerosolised granulocyte-macrophage colony-stimulating factor is safe and effective in treating pulmonary alveolar proteinosis providing an alternative to whole-lung lavage or subcutaneous granulocyte-macrophage colony-stimulating factor.

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