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Jointly provided by the National Association for Continuing Education and DKBmed
Supported by an independent educational grant from Gilead Sciences, Inc.

Table of Contents


This monograph was adapted from the live webinar Cystic Fibrosis Virtual Roundtable: Challenges in Treating Lung Infections. The learning objectives for this activity are:

  • to evaluate currently available data on Pseudomonas aeruginosa therapies
  • to discuss treatment options when first line chronic inhaled antibiotics fail
  • to apply current information to design effective long-term alternating inhaled antibiotic therapy schedules

Introduction

PREVALENCE OF RESPIRATORY MICROORGANISMS BY AGE COHORT

The lung in a patient with CF is complex. The graph above from the CF Patient Registry demonstrates the prevalence of various bacteria within the airways.1In younger children, Haemophilus influenza and Staph. aureus are the most common organisms; however, as CF patients age, Pseudomonas aeruginosa becomes much more prevalent. There are a number of other gram-negative bacteria that are also present.
A great deal of focus has been put on treating Pseudomonas infection. Several pieces of evidence show that CF patients who are infected with Pseudomonas aeruginosa have greater lung function decline and earlier mortality.


P. aeruginosa & Lung Function

The graph above is from a study that included a cohort from Sweden and looked at patients with and without pancreatic insufficiency.2 As illustrated in the graph, those people who are infected with Pseudomonas have a faster rate of decline in lung function as measured by FEV1 compared with those who are not infected with Pseudomonas.

Aerosol Antibiotics for CF Airways Disease

The CF airway faces several challenges. Abnormal secretion associated with CF lead to poor mucociliary clearance, chronic inflammation, and airways obstruction. Lung cultures are obtained on a regular basis when patients are treated at clinic. Early in life, patients are not infected with Pseudomonas. However, over time, intermittent infection occurs. During this period, eradication is attempted to eliminate or delay chronic infection with Pseudomonas. Ultimately, though, chronic infection occurs.
In the early period, when Pseudomonas is initially found, eradication therapy has been shown to be quite effective. The Cystic Fibrosis Foundation has recommended the use of inhaled tobramycin 300 milligrams twice daily for 28 days.3 Other approaches are likely to be effective. Data from the ALPINE Study suggest that inhaled aztreonam can be effective in eradication.4

P. aeruginosa Prevalence Is Decreasing

Because of this approach to eradication, the prevalence of Pseudomonas has been decreasing in the CF population. This is meaningful because failure to eradicate Pseudomonas is associated with worse outcomes. Data from the Early Pseudomonas Infection Control (EPIC) trial, which followed 838 children before and after their initial isolation of Pseudomonas (mean 4.6 years), show that 51% patients eventually acquire Pseudomonas.5 Despite widespread eradication therapy, a 40% increase in exacerbations was observed. Crackles or wheezes were also more common. Further, increased risk of MRSA, S. maltophilia, and A. xylosoxidans was observed after initial Pseudomonas infection. There was no difference in lung function or nutritional outcomes, however. The factors associated with eradication failure were mucoid phenotype of the Pseudomonas, as well as an altered biofilm or defective quorum sensing. 6

Inhaled Antibiotics for P. aeruginosa – corrected, with Yaxis labels

When eradication fails, chronic suppression is implemented, typically with inhaled antibiotics. Data from one of the original trials on inhaled tobramycin showed dramatic improvement in lung function with a 28-day on/off cycle for inhaled tobramycin.7 Improvements in lung function were maintained over time compared to the placebo.

Aztreonam Lysine

Aztreonam is also an inhaled antibiotic approved for use in the United States. Data from a 2013 trial, illustrated above, demonstrates an improvement in lung function, compared with tobramycin, in three cycles of the drug.8
In Europe, other inhaled antibiotics include colistin and levofloxacin. Colistin is used in the United States in off-label form. Inhaled liposomal amikacin is being developed for another indication but it may be effective for Pseudomonas as well.
The continuous alternating approach has emerged as a common treatment option, rather than using an 28-day on/off cycle. Trials have shown that during the “off” periods, patients lose lung function that was gained during the “on” periods. Alternating aztreonam and tobramycin preserves lung function that would be lost during the off periods of an on/off cycle. A double-blind trial investigating the value of this therapy was attempted, with the goal of comparing the effectiveness and safety of continuous alternating therapy with the traditional intermittent therapy.9 Participants were treated with three cycles of 28 days of aztreonam or placebo alternating with 28 days of tobramycin. However, only 90 subjects of the planned 250 were enrolled because continuous alternating therapy (CAT) was already becoming standard practice at the time of study enrollment. Therefore, the study was underpowered to detect statistical difference in the primary endpoint (reduced exacerbation rates). The trial did show a 25.7% reduction in exacerbation and 35.8% reduction in hospitalization.

 The Microbiome is Complex and Dynamic

P aeruginosa is not the only bacterium affecting the CF airway. Bronchoalveolar samples for patients with CF illustrate the various bacteria present in the airway.10 Further, the bacteria composition changes over time associated with exacerbations and aging.
Azithromycin is also used in adjunct therapy. Although azithromycin is an antibiotic, its anti-inflammatory properties are thought to be effective in improving lung function and, more importantly, reducing exacerbations.

Azithromycin and Tobramycin

This graph above illustrates the effect of azithromycin on tobramycin.11 This retrospective data looking at the change in FEV1 with inhaled antibiotics shows that in those people not taking azithromycin (the two left-most bars), tobramycin and aztreonam have a similar effect. However, in people receiving azithromycin, the FEV1 change with tobramycin was less. A large prospective trial, Testing the Effect of Adding Chronic Oral Azithromycin to Inhaled Tobramycin in People with CF (TEACH), is underway to confirm these data.

Restoring CFTR Function Decreases P. aeruginosa

The landscape of CF therapy is changing. Modulator therapies, which can affect infection rates, are now becoming widely used. A study from the GOAL investigator shows real-life data on the effect of ivacaftor in Pseudomonas infection.12Before staring ivacaftor, approximately half of the cohort was infected with Pseudomonas; however, after ivacaftor initiation, the infection rate decreased.
In summary, infection affects pulmonary outcomes in people with CF. Inhaled antibiotics are effective in treating people with CF. The airways contain a complex, dynamic microbial community, and that CFTR modulator therapies impact airway microbiology.

CASE PRESENTATIONS



CASE ONE

Peter J. Mogayzel, Jr., MD, MBA (Moderator): The first case is a 16-year-old girl who has two copies of F508-del. Her BMI is in the 25th percentile, and her lung function is good with an FEV1 at the 85th percentile. Her airway cultures have consistently grown P aeruginosa. Her daily medication regimen includes dornase alfa once a day, inhaled tobramycin twice a day every other month, and albuterol; as well as oral azithromycin on Monday, Wednesday, and Friday. She uses high-frequency chest wall oscillation for airway clearance and is active in sports. She was hospitalized two years ago for a pulmonary exacerbation.

This patient appears at clinic for her routine quarterly visit. Over the past year, she has experienced a gradual decline in lung function. She has a minimal increase in her cough, but she does not express concern about this cough at today’s visit.

Possible options for therapy include (1) continue the current therapies and have her come back to clinic in three months; (2) treat for an acute exacerbation; (3) change her antibiotic therapy regimen; (4) add hypertonic saline or other changes to her airway clearance regimen; (5) order diagnostic testing; and (6) discuss adherence, technique, or other psychosocial circumstances that may be impacting her care.

How would you proceed with this patient?

PATRICK FLUME, MD: I am always concerned about drops in lung function. This appears to be a rather typical case: it is common for a patient to not describe much change in their symptoms and yet when you look back at the trend in lung function, you notice a steady decline. Adolescence is a particularly vulnerable time in a patient’s life in and is when, in my opinion, we need to be most aggressive. It’s important to recognize that even though her lung function has not declined sharply, there is a downward trend.

Of the possible therapy options you suggested, the one incorrect option is to do nothing and see this patient in three months, but there is a choice between an acute treatment or a change in her chronic therapy.

LISA SAIMAN, MD: I agree. This patient is a teenager and, presumably, she’s making transitions to some self-care, which can be challenging. She is also busy with school and extracurricular activities, so I would be worried about her adherence to her treatment regimen. I would consider admitting her to the hospital and treating her with intravenous antibiotics. She experienced a significant drop in lung function over the past year and it is possible that she may not recover entirely from that drop.

MOGAYZEL: How do you decide between acute therapy and change in chronic therapies?

FLUME: This patient is part of a particularly vulnerable group. In patients who start off with good lung function, interventions are often delayed. But hospital admission and acute therapy can send a clear message that not only are we trying to turn things around, but also that these drops in lung function are serious. We measure lung function for a reason. If it is dropping, then we should act upon it.

Many patients and families may resist coming into the hospital. In that case, we have to make a change to chronic therapy and then see the patient in the short term so we can evaluate if the treatment is effective and making a difference.

MOGAYZEL: One of the treatment options is changing the antibiotic. This patient grows Pseudomonas. Is there any value in switching to different inhaled antibiotic or adding another inhaled antibiotic?

SAIMAN: Before making a change to her chronic therapy, I would explore what is going on in this girl’s life. How is she managing her high school, her extracurricular activities, her social life? Is she taking the medications? I would be reluctant to change some part of her regimen if she is not taking what is prescribed. This conversation should be held both with and without a parent in the room. Again, this patient is in a time of transition, when she is— or should be — taking on some of her care herself. It is very challenging.

It is also important to make sure that she understands each part of her regimen and the rationale for it. She needs to have an understanding of what each part of regimen is doing.

FLUME: If we assume that this patient is fully adherent to the regimen, then our choices are to add something (such as hypertonic saline), to change something, or do more diagnostic testing just to make sure that we are not missing something else, such as diabetes, a new organism, or ABPA.

Regarding inhaled antibiotics, we know that patients may develop an attenuated response to continued use of antibiotics over time; therefore, changing their antibiotic regimen can be advantageous. The same phenomenon is observed with intravenous therapy; sometimes patients are simply less responsive to the drugs they have been using and are more responsive to a change.

Some experts and studies have questioned whether the typical month on/month off regimen with inhaled antibiotics is the ideal regimen to prescribe. An argument against that on/off cycled approach is the “sawtooth” pattern changes of lung function observed during these cycled regimens, in which lung function drops during the off month. This observation led people to move toward a continuous inhaled antibiotic approach, with either one antibiotic or alternating antibiotics (eg, inhaled tobramycin alternating with inhaled aztreonam).

The study of continuous alternating therapy (CAT) regimen was based on an earlier study of inhaled aztreonam, which showed that patients who had previously been receiving tobramycin experienced an increase in lung function when they were switched to aztreonam. The CAT study was designed to compare outcomes for patients who were using CAT vs patients on a 28-day on/28-day off regimen. All of the patients were told to use inhaled tobramycin every other month, and they were randomized to use inhaled aztreonam or placebo during the interim months. However, the study was unable to enroll a sufficient number of patients because many physicians had already adopted a CAT regimen, and they were unwilling to possibly randomize their patients to placebo. The study was stopped early and was underpowered to demonstrate a statistically significant difference, but trends toward fewer exacerbations were observed. Although we do not have absolute evidence that CAT is a preferred or better regimen, registry data show that an increasing number of patients are on two antibiotics on a continuous regimen. Of course, registry data are helpful in developing hypotheses, but it is risky to infer that the observations from the registry are the absolute truth. Generally, physicians are more inclined to recommend a continuous regimen in patients who seem to be sicker, so a treatment bias may be involved in patient selection.

MOGAYZEL: How do you factor in the additional burden of another therapy when making a treatment recommendation to patients and their families?

FLUME: Again, it is very important to determine how patients are adhering to the treatment plan, because if we add therapies when the patients are not actually adhering to existing therapies, we are not making progress. But when recommending an additional treatment, it must be put in context of the overall regimen, including time burden and financial cost. For example, when adding an inhaled regimen, whether it’s hypertonic saline or moving to a CAT regimen, treatment time is added to that person’s already busy day. In particular, if we switch to a CAT regimen with alternating tobramycin and aztreonam, now the patient has two different nebulizers, which add cleaning responsibility, the need for more education, and possibly some confusion. That is why engaging in conversation with the patient and the family is particularly important when trying to determine how to obtain the best outcome.

MOGAYZEL: How do you approach the decision between treating the infection differently with a change in antibiotics versus enhancing airway clearance with hypertonic saline?

FLUME: I consider how responsive the patient’s airway is to aerosol therapy. If, for example, the patient reports that she gets chest tightness or increasing cough when she’s using her tobramycin, I might be a little less reluctant to use hypertonic. On the other hand, if she’s a sputum producer — and I will assume that she is, based on the cultures — it might be the very thing she would benefit from. Some patients love a drug like that, and some people just really hate it because it adds to their treatment burden.

SAIMAN: Another consideration is that the delivery system for hypertonic saline is simpler than that of inhaled aztreonam, but the patient still has to worry about cleaning it.

FLUME: It is clear that none of the possible treatment options are the only absolutely correct response, but doing something as opposed to doing nothing is the right thing to do. And, of course, whatever we do, we have to follow up on it in the short term.

SAIMAN: Engaging the patient as a young adult and helping her be part of the decision-making process are crucial because soon she will potentially be living outside of the home, in college, and that is a vulnerable time for a lot of people with CF.

MOGAYZEL: I agree. Especially when the patient is an adolescent, it is very important to make sure the patient and family agree that the changes to the regimen will be beneficial.

SAIMAN: We did not explore the possibility that this patient has a new positive culture for nontuberculous mycobacteria (NTM). The adolescent age group has a relatively high prevalence of NTM, particularly Mycobacterium abscessus, so it is important to make sure we explore that possibility.

CASE TWO

What if lung function is stable but new organism is present?

MOGAYZEL: Let us rework this case a little and assume this same young patient now has another organism, such as MRSA, nontuberculous mycobacteria (NTM), or some other gram-negative bacterium, such as Stenotrophomonas maltophilia. How should we treat this patient? Again, the options are to continue with current therapy; immediately attempt eradication of the organism; repeat the culture; do additional testing, maybe get a CT scan or some other test that may be helpful; or change existing therapy.

SAIMAN: My approach would be different for different organisms, so it’s important to know which organism is found. If, for example, if she had a positive culture for NTM, it is extremely important to repeat the culture. Emerging data suggest that about one-third of people have transiently positive cultures. This patient is a sputum producer, so we should get a good-quality specimen. If she were to be repeatedly positive, then it would be time to explore whether something else is contributing to her deterioration before launching into treatment. Also, attempting eradication without an evidence base for doing so may not be the right action.

FLUME: The ongoing, multicenter PREDICT study, an observational study evaluating clinical outcomes for patients with CF who have cultures positive for NTM, may shed light on this issue.13 Are these patients’ cultures intermittently or persistently positive for NTM? What are their clinical scenarios? This approach is appropriate, because we currently do not have the epidemiology to know whether or not attempting eradication is correct. The ATS-IDSA guidelines for treatment include the caveat that treatment should not be considered until other infections treated and the patient has bronchiectasis.

SAIMAN: This and similar trials will teach us how to approach other problematic pathogens or microorganisms that may not be pathogenic in every single patient with a positive culture.

MRSA has similar questions around it. Again, a substantial proportion of people do not have persistently positive cultures. The eradication regimen for MRSA was quite onerous, yet it did not show any long-term clinical benefit. We still do not know the optimal way of treating MRSA when it’s contributing to an exacerbation, but studies are ongoing to help us learn more about that.

FLUME: We can all agree that P aeruginosa infection should be treated by eradication for early infection or chronic suppressive therapy, but whether the same strategy applies for other organisms is a legitimate question that is still debated. MRSA has our attention because registry data suggest that MRSA is associated with worse outcomes. But we still have to demonstrate that eradication or chronic suppressive therapy results in better outcomes. The STAR-too study evaluated eradication but was terminated early because of the significant reduction in participants with positive MRSA culture at day 28 in the treatment arm. Clinical outcomes after day 28 were difficult to interpret because of the high rates of antibiotic use in both the treatment and observational arms.14 An ongoing study is evaluating effects of aerosolized or inhaled vancomycin on clinical outcomes. The important point is that we need to investigate effects of treatment, not simply adopt a treatment strategy until we have some evidence that treatment will make a difference.

MOGAYZEL: We have a tendency to try to treat because we want to make people healthy, but it is not always clear that we need to treat particular infections; and if we do need to treat infections, what the optimal approach is. Returning to the discussion of NTM, do you think about NTM differently if you are talking about M abscessus versus MAC, or are they the same?

FLUME: M abscessus receives more attention in the CF world for a few reasons. First, it seems to be more prevalent in the CF population, whereas in the general population, MAC is far more prevalent. Second, people think that M abscessus is a worse pathogen, to the point where some patients may no longer be eligible for lung transplant even though the guidelines indicate that it should not be a contraindication. It is understandable why clinicians would want to take a much more aggressive approach when they first find it.

Having said that, we do not have uniform screening across the country. Some centers are actively screening for NTM, whereas in others, screening has not become a standard approach.

SAIMAN: Screening for NTM is recommended in the guidelines, of course.

FLUME: We have heard from our colleagues from National Jewish that MAC may be equally worrisome and associated with worse outcomes; therefore, they urge that clinicians pay attention not only to M abscessus but to NTM in general.

SAIMAN: The treatment regimens are, of course, different. However, the approach is the same in that we first must confirm that the bacteria are really there and then assess the clinical picture. It is important to evaluate other potential contributors to deterioration and then make a well-informed decision. The treatment regimens are quite onerous. M abscessus requires intravenous therapy for quite some time, with a lot of potential toxicity. It is very important to make a sound decision for the patient’s sake.

MOGAYZEL: Would you stop macrolides used for as antiinflammatory therapy if a patient has a culture that grows an NTM?

SAIMAN: Absolutely. Macrolide antibiotics are the workhorses of the regimen, and there are emerging data that macrolide resistance occurs. Intrinsic mechanisms of resistance are induced in the presence of macrolides, and we need to know that, because patients will not respond. Many patients have macrolide-susceptible NTM despite taking macrolides regularly, but if we lose the ability to use macrolides, the regimen will be much more complex.

FLUME: A large proportion of patients with M abscessus have macrolide-resistant bacteria. Standard methodologies will not detect resistance, so gene testing should be performed and should become routine practice, along with identifying subspecies so we know specifically which organism is involved. The Cystic Fibrosis Foundation sponsors a program in which these organisms can be sent to the National Jewish Advanced Diagnostic Laboratories for further investigation.

CASE THREE

25 y/o

MOGAYZEL: Instead of an adolescent, now our patient is a 25-year old woman with an FEV1 of 50% predicted, which is a 10% decline from one year ago. How do you approach his older patient with worse lung function? Again, the options are to not change her regimen, treat for an acute exacerbation, change the antibiotics, add hypertonic saline, order diagnostic testing, or discuss adherence and other aspects of her life that may be affecting her declining lung function.

FLUME: The short answer is that the strategy does not change. If there is evidence of decline, intervention is warranted. We need to find out what is working and what is not working. I sometimes argue that intervention in the hospital is superior to intervention outside of the hospital. Even though many of those therapies can be done at home, patients in the hospital have nothing to do except pay attention to their health.

But I also think we need to probe to find out if there are other issues, such as depression or anxiety or financial issues that need to considered when making any treatment decisions.

SAIMAN: I agree with that. We are now understanding that anxiety and depression are prevalent in people with CF and their parents. In this setting, I would be more likely to hospitalize this 25-year-old patient than I would a younger patient. Her lung function is not good and because she is probably quite busy, her adherence is likely to be challenged.

I would revisit all of the airway clearance techniques and make sure she understands the importance of each and every drug. The data suggest that even when people say that they are taking all their medications, they are actually not doing so. I would assume that this patient is not able to manage the entire regimen, particularly if she has children.

MOGAYZEL: How does the concept of antibiotic-resistant bacteria change your approach to inhaled antibiotic therapy?

SAIMAN: As an infectious disease doctor, I think of resistance differently for CF patients. For CF patients, the susceptibility panels that come back from the laboratory are not always meaningful. We have known for a long time that people will get better on a regimen even if the susceptibilities panel shows resistance. In vitro susceptibility testing does not help much with clinical outcomes. When administering a drug by the aerosol route, a large concentration of the antibiotic within the lung, targeting the site of infection, can often overcome the resistance mechanisms

FLUME: I am involved in a program dedicated to gaining greater understanding of antimicrobial resistance in CF. It is important to know which organisms are inherently resistant to an antibiotic and those that are not. But the issue in CF is how informative the culture result actually is because there are several reasons why the drug might not work in the patient population.

A culture is helpful in identifying genus and species of a new pathogen, but it’s not as predictive of susceptibility and response to antibiotics.

In a patient such as the one in our case, the reason to switch an antibiotic or to move to a different regimen like a CAT regimen is because the patient is not responding clinically the way we would hope. I would empirically test for effectiveness, give her another drug, and then check for response.

I am more likely to change a medication because it is not working than I am to change it because the culture may show that the bacterium is highly resistant to the medication. For example, if the bug were resistant to aztreonam, I would still try using inhaled aztreonam in that patient to see if there’s a clinical response. This is not an easy concept for most people to grasp, but it is what empirical observations have taught us over time.

SAIMAN: An international initiative being conducted around the world by CF investigators is developing a shared vocabulary with case definitions for resistance and susceptibility. That will be very valuable, because how in vitro susceptibility affects clinical efficacy is not clear at this point.

MOGAYZEL: When talking about changing therapy or adding new therapy, how does radiology factor into your decision?

FLUME: A CT scan can be helpful in certain clinical situations, such as when I am worried about bad mucous plugging or the presence of a new organism that I might not be getting by sputum cultures. A CT scan is more helpful than a chest x-ray, unless there were no breath sounds coming into a certain area of the chest. If I need to use bronchoscopy to identify a bug in a nonsputum producer, a CT scan can tell me exactly where to go with the bronchoscope.

MOGAYZEL: Is there any value to routine CT scans?

FLUME: I do not obtain routine CT scans, but they are used when clinically indicated.

MOGAYZEL: I agree and tend to have a similar approach of using CT scans when things are not going as expected or I am trying to identify other problems.

SAIMAN: Patients and families may be sensitive about radiation exposure, so we have to present a sound rationale for why we are requesting a scan.

MOGAYZEL: What about using azithromycin as an adjunct therapy for people with P aeruginosa and the relationship between azithromycin and the effectiveness of tobramycin. How do you advise people about azithromycin?

SAIMAN: This is an interesting subject because post hoc analyses of the comparator trial of aerosolized aztreonam and aerosolized tobramycin showed what appeared to be an adverse effect of azithromycin in the people who were on aerosolized tobramycin, and this was not noted in the study group of aztreonam and azithromycin. The authors showed biologic plausibility to that observation because it appears that azithromycin stimulates the production of efflux pumps, which pump out the aminoglycosides, making it less active. The ongoing TEACH trial will be helpful because we will be able to observe if the in vitro effects are consistent with what post hoc analyses demonstrated. If they are, we should change the way we approach those regimens.

We all know that it is important to continually ask ourselves hard questions about long-term benefit and unanticipated adverse outcomes of the therapies that we use.

FLUME: We make observations in the laboratory, and we find compelling clinical data that fit with that story, but we still have to complete a study to find out the effects. We cannot simply stop these therapies without a trial because macrolides have been beneficial. We can debate whether they work by an antibiotic effect or an antiinflammatory effect, but a clinical trial demonstrated a clinical benefit in reducing exacerbations, which is perhaps the most important effect to patients.

Subsequent to that, there was concern about using chronic macrolides and perhaps increasing the risk of mycobacterial infection because of laboratory data, but the registry data suggest there is a protective effect. I look forward to reading the results from the TEACH trial so we can learn more about how to use these drugs together.

MOGAYZEL: We treat people with a lot of different medications, and the interactions are sometimes unknown over long periods of time. It is important to not just assume things will continue to work as we anticipated from an earlier trial, which is why we have to study these therapies and disseminate the results.

Q & A

ANNOUNCER: We will now move to the question and answer session. If you have any questions, please type them into the action center and they will be addressed in the order in which they are received. Peter, the floor is yours.

slide 1

DR. MOGAYZEL: We’ve had a number of very interesting questions from our audience. The first is about modulator therapies. We have a number of new drugs that have come onto the market and future ones in development. Patrick, what’s been the information about how the modulators may affect the bacterial environment, and perhaps I would think about changes that we’ve seen on future therapies or the way we approach infections.

DR. FLUME: Thank you. The CFTR modulators have been very interesting. Obviously we’re happy to see them work for our patients and improve lung function, but we’re also seeing lots of other clinical benefits. One of those is the other impacts on the lung, like improving mucociliary clearance, and also the potential effects on the microbiology we get from cultures. Early on we’re beginning to see those numbers are evolving. I think over the next several years we’ll see some really interesting changes in which patients have chronic infection or time to first infection, and we’ll have a lot to talk about there.

On the other hand, I don’t know that it should influence how you make decisions in terms of therapies. As you put them on a modulator, your patients might ask what therapies they can stop. If they still are growing Pseudomonas in their cultures, I’m not sure I would advise them to stop their inhaled antibiotics. For me the decision about how I use those antibiotics and in which patients I use them is still based on their clinical status and microbiology.

slide 2

MOGAZEL: That makes a lot of sense. Lisa, do you think we’ll be seeing changes in the whole population as these drugs are used in younger and younger patients?

SAIMAN: Excellent question. I think we just need more time. We’re poised to do those studies, and that’s incredibly important. A study that’s ready to go called PROMISE will look at all the things that Patrick just mentioned, not only things like mucociliary clearance, but also changes in microbiology over time. And what you’re saying about the younger child is very important because they won’t have established infections. So it’s probable that the impact of the CFTR correctors will be different depending on when they’re begun.

So in the young child they may never be infected, we may have a substantial delay before infection, and in people who already have established lung disease and infections, we’re not 100% sure they will lose those infections. I think the best news is, we’re poised to be able to answer those questions.

slide 3

MOGAZEL: One of the challenges providers often face is how to interpret resistance patterns in Pseudomonas using inhaled antibiotics. I know, Patrick, you’ve given a lot of thought to resistance and how to interpret those numbers. What do you think we should do with respect to inhaled antibiotics?

FLUME: There’s a lot that we know empirically about resistance, and I’m not sure we have all the answers to explain our observations, but, classical teaching would be if your bug is resistant to the drug you’re using, you would not expect a clinical response. But our experience in CF is that we see patients with resistant organisms improve in spite of it, or sometimes patients who seemingly have susceptible organisms that don’t respond to those therapies, so we often find ourselves shifting those medications around.

We have a working group addressing this and we made our first presentations at the last North American meeting about the progress from the group. I’m pleased to say that our second manuscript has been accepted for publication and is now online in the Journal of Cystic Fibrosis. It was a systematic review of the literature to demonstrate the prognostic ability of culture data and response. The reality is, it’s not.

What will be forthcoming is the consensus recommendations on how to use those data. It’s not that physicians aren’t interested in tracking resistance; they’re more interested, however, in the species, which bugs are present in the sputum and the clinical response. So with more specificity to your question, if I, for example, have a patient with Pseudomonas and that bug is resistant to tobramycin, that would not deter me from using a drug like inhaled tobramycin in those patients. Our experience is, in general, those patients will respond.

I think probably the most valuable of information is the species results, and then we will find out again more about how to use resistance data. But as a practice, our center orders susceptibility testing less and less frequently as time has gone on.

SAIMAN: Peter, I’d like to also add that the audience needs to understand that the break point, the number we use to determine if something is susceptible or resistant, is based on bloodstream infections and also based on the concentration of an antibiotic that can result in toxicity, such as nephrotoxicity or ototoxicity, in the example of aminoglycosides. But those parameters and those paradigms are not relevant when giving a drug by the aerosol route, where you’re giving much, much higher concentrations that can overwhelm typical mechanisms of resistance and are not associated with systemic absorption and the toxicities that I just mentioned. So that is another really good reason why we shouldn’t make the correlation between the resistance determination from a microbiology report and whether a drug will work when given by the aerosol route.

MOGAZEL: You make a very good point, Lisa. I think we sometimes forget exactly how these values are obtained by the microbiology lab. We’ll wrap up our questions now, and this has been a very helpful discussion for our participants.

MOGAZEL: Thank you for participating in this program. To receive CME credit complete the post test and evaluation forms. I want to thank Lisa and Patrick for participating in this really great discussion.

SAIMAN: You’re welcome, it was fun.

FLUME:Thank you.

References

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  3. Mogayzel PJ, Naureckas ET, Robinson KA, et al. Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc. 2014;11(10):1640-50.
  4. Tiddens HA, De boeck K, Clancy JP, et al. Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study. J Cyst Fibros. 2015; 14(1):111-9.
  5. Zemanick ET, Emerson J, Thompson V, et al. Clinical outcomes after initial pseudomonas acquisition in cystic fibrosis. Pediatr Pulmonol. 2015;50:42-8.
  6. Mayer-Hamblett N, Ramsey BW, Kulasekara HD, et al. Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis. Clin Infect Dis. 2014;59:624-31.
  7. Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340(1):23-30.
  8. Assael BM, Pressler T, Bilton D, et al. Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial.J Cyst Fibros. 2013;12(2):130-40.
  9. Flume PA, Clancy JP, Retsch-bogart GZ, et al. Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis. J Cyst Fibros. 2016;15:809-815
  10. Frayman KB, Armstrong DS, Carzino R, et al The lower airway microbiota in early cystic fibrosis lung disease: a longitudinal analysis. Thorax. Published Online First: 09 March 2017. doi: 10.1136/thoraxjnl-2016-209279
  11. Nichols DP, Happoldt CL, Bratcher PE, et al. Impact of azithromycin on the clinical and antimicrobial effectiveness of tobramycin in the treatment of cystic fibrosis. J Cyst Fibros. 2017;16(3):358-366.
  12. Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014;190(2):175-84.
  13. PREDICT: NTM observational study
  14. Muhlebach MS, Beckett V, Popowitch E, Miller MB, Baines A, Mayer-Hamblett N, Zemanick ET, Hoover WC, VanDalfsen JM, Campbell P, Goss CH; STAR-too study team. Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial.Thorax. 2017 Apr;72(4):318-326.

Jointly provided by the National Association for Continuing Education and DKBmed
Supported by an independent educational grant from Gilead Sciences, Inc.

Do you have a patient with CF that has a particularly challenging lung infection?

Join Peter Mogayzel, Jr., MD, PhD as he leads a case-based discussion with Patrick Flume, MD and Lisa Saiman, MD on challenges in treating lung infections. After a short update on the management of patients with declining FEV1, they address potential treatment options, including reinforcing adherence, working on inhaler techniques, changing inhaled antibiotics, and considering a continuous, cycled, or intermittent therapy approach. New evidence from real-world and other studies will be presented, and viewer questions will be answered at the end of the program.


Start Program

Jointly provided by the National Association for Continuing Education and DKBmed
Supported by an independent educational grant from Gilead Sciences, Inc.

Program Directors

Peter J. Mogayzel, Jr, MD, PhD, MBA

Professor of Pediatrics
Director, Cystic Fibrosis Center
Johns Hopkins University School of Medicine
Baltimore, MD



Dr. Peter Mogayzel has been the Director of the Cystic Fibrosis Center since 2002 and Medical Director of the Pediatric Lung Transplantation Program since 1998. An Associate Professor of Pediatrics, he attended Brown University and received his M.D. and Ph.D. degrees from Boston University. He completed his pediatric residency at the University of Washington, and pediatric pulmonary and pediatric critical care fellowships at Johns Hopkins in 1998 before joining the faculty. The thrust of his research is on the regulatory properties of the CFTR gene. He is also a lung transplant specialist whose work in that field was showcased on ABC’s documentary Hopkins 24/7


Patrick Flume, MD

Professor of Medicine and Pediatrics
Medical University of SC
Charleston, South Carolina





Patrick Flume is a Professor of Medicine and Pediatrics at the Medical University of South Carolina. He oversees a rapidly growing Cystic Fibrosis Center, including the largest adult CF program in South Carolina. He serves as the Powers-Huggins Endowed Chair for Cystic Fibrosis.

He is recognized by the national and international CF community having served on the CF Foundation Center Committee, the Adult Care Consensus Committee, and the Advisory Task Force on Adult Issues, the Professional Education Committee, and as founding co-chair of the CF Foundation Pulmonary Practice Guidelines Committee.

His primary clinical interests are in CF, bronchiectasis and non-tuberculous mycobacteria, and he leads an active clinical research program in all of these areas. He is engaged in the MUSC Clinical and Translation Science Award (CTSA) serving as the Program Director for the Research Center, member of the Executive Committee for the CTSA, and chair of the Scientific Review Committee.



Lisa Saiman, MD, MPH

Professor of Pediatrics
Division of Pediatric Infectious Diseases
Columbia University Irving Medical Center
New York, NY



Dr. Lisa Saiman is a Professor of Pediatrics at Columbia University Irving Medical Center in New York, NY. She joined the faculty of the Division of Pediatric Infectious Diseases in 1989 and received her Masters of Public Health from the Mailman School of Public Health at Columbia University in 1999. Dr. Saiman is an Attending Physician and the Hospital Epidemiologist at NewYork-Presbyterian Morgan Stanley Children’s Hospital. For over 25 years, cystic fibrosis has been Dr. Saiman’s primary research and clinical interest with a focus on the infectious complications of CF and infection prevention and control for this population. She served as the co-chair for the 2003 and 2013 Guidelines for Infection Prevention and Control for CF as well as the Principal Investigator for two multicenter azithromycin trials in CF. Dr. Saiman also serves on the Planning Committee for the North American CF Conference and the CF Foundation’s Patient Registry committee. Dr. Saiman is a member of the Society of Healthcare Epidemiology of America, the Infectious Disease Society of America, the Pediatric Research Society, the Society of Pediatric Research (elected) and the Pediatric Academic Society (elected). In addition, she serves as an advisor to the NY State Health Department and to the Cystic Fibrosis Foundation on matters related to infectious diseases, microbiology, and infection prevention and control.

Jointly provided by the National Association for Continuing Education and DKBmed
Supported by an independent educational grant from Gilead Sciences, Inc.

CME/CE

Accreditation Information

Jointly Provided by Postgraduate Institute for Medicine and DKBmed, LLC
This activity is supported by an independent educational grant from Gilead Sciences Inc.

Target Audience
This activity has been designed to meet the educational needs of clinicians who treat patients with cystic fibrosis.

Physician Continuing Medical Education

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and DKBmed, LLC. Postgraduate Institute for Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME).

Credit Designation Statements

The Postgraduate Institute for Medicine designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Estimated time to complete activity: 1.0 hours

Educational Objectives

After completing this activity, the participant should be better able to:

  • Evaluate currently available data on Pseudomonas aeruginosa therapies.
  • Discuss treatment options when first-line chronic inhaled antibiotics fail.
  • Apply current information to design effective long-term alternating inhaled antibiotic therapy schedules.

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.
The faculty reported the following financial relationships or relationships they or their spouse/life partner have with commercial interests related to the content of this continuing education activity:

Faculty / Presenter Reported Financial Relationship

Peter J. Mogayzel, Jr., MD, PhD
  • Grant Funding: Vertex Pharmaceuticals, Inc. and Gilead Sciences, Inc.
Patrick Flume, MD
  • Consulting Fees: Bayer Health AG, Corbus Pharmaceuticals, Eloxx Pharmaceuticals, Horizon Pharma, Insmed, McKesson, Novartis, Proteostasis Therapeutics, Vertex Pharmaceuticals, Inc.
  • Contracted Research: Bayer Health AG, Corbus Pharmaceuticals. Cystic Fibrosis Foundation Therapeutics, Galapagos, Insmed, National Institutes of Health, Novartis, Novoteris, Proteostasis Therapeutics, Sound Pharmaceuticals, Inc., Vertex Pharmaceuticals, Inc.
Lisa Saiman, MD
  • Royalty: UpToDate (<$50 per year)
  • Consulting Fees: CF Foundation
  • Other: Assisted ABComm, Inc. in developing slide deck for CF Grand Rounds; Assisted Gilead with writing abstracts for North American CF Conference on their Phase IV post-licensure study for aerosolized aztreonam.

The planners and managers reported the following financial relationships or relationships they or their spouse/life partner have with commercial interests related to the content of this continuing education activity:
The PIM planners and managers have nothing to disclose.
The following DKB planners and managers Stan Pogroszewski and Rachel Deerr hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Method of Participation and Request for Credit

There are no fees for participation in this CME activity. To receive credit, participants must 1) read the learning objectives and disclosure statements, 2) complete the educational activity and 3) complete the post-test and activity evaluation form, including the certificate information section. Physicians and social workers must attest to the amount of time they spent on the activity.
Media: Internet

Enduring Materials

  • Release Date: 2/11/19
  • Expiration Date: 2/10/20
  • Estimated time to complete activity: 1.0 hours

Hardware & Software Requirements
PC: Internet Explorer (v9 or greater), Chrome or Firefox
MAC: Safari
Monitor settings: High color at 800 x 600 pixels, Sound card and speakers, Adobe Acrobat Reader.

Copyright © 2018. PIM and CF Virtual Roundtable.
Presented by PIM in collaboration with DKBmed

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ONLINE PRIVACY POLICY

DKBmed, LLC (DKBmed) operates a network of continuing health care educational activities and their related websites and apps (Programs). For a list of all the programs within our network, see http://www.DKBmed.com/programs. This is the official privacy policy (Privacy Policy) for all DKBmed Programs, and this Privacy Policy forms a part of your legal agreement with us under the DKBmed Terms of Use.

PLEASE READ THIS PRIVACY POLICY CAREFULLY, AS IT DESCRIBES HOW WE COLLECT AND USE INFORMATION WE COLLECT ABOUT YOU ONLINE AND UNDER WHAT CIRCUMSTANCES WE SHARE INFORMATION ABOUT YOU.

DKBmed is committed to keeping accurate confidential, secure, and private any and all personal information collected of those individuals who visit our websites and use our online facilities and services. Our Privacy Policy has been designed and created to ensure those affiliated with DKBmed, of our realization of and commitment to our obligation not only to meet, but to exceed most existing privacy standards.

THEREFORE, this Privacy Policy shall apply to DKBmed and thus it shall govern any and all data collection and use thereof. By using DKBmed.com and any DKBmed Programs you thereby acknowledge that you are familiar with and you agree to the following data procedures expressed within this agreement.

Collection of Information
When you sign on to our Website or participate in our Programs, we collect the following voluntarily provided information, which may include your name, address, email address, profession, specialty, phone, and information for your membership in the National Association of Boards of Pharmacy and/or the American Board of Internal Medicine. In certain circumstances related to the use of our services we may ask you for your date of birth (month/day) and/or your National Provider Identifier (NPI) and/or ABI identification number. This information may be used when you participate in DKBmed Programs or purchase products and/or services from DKBmed to deliver the services and Programs you have requested. This data is collected on the basis of our need to fulfill the contract you have entered into with DKBmed when you decided to sign on to our Website and use our services and/or Programs. We need this information so we can provide you the services and/or Programs you have requested.

Cookies
Currently the only information about you that we collect through cookies is email address, name, and subscription details. This data is used for the sole purpose of automatically logging in users when they visit the Programs or website. This data is processed based on our legitimate business interest to maintain the proper functioning of our services and to provide you with better user experience.

Third-party cookies
DKBmed uses third-party vendor remarketing tracking cookies, including the Google Adwords tracking cookie. This means we will continue to show ads to you across the internet, specifically on the Google Content Network (GCN). As always we respect your privacy and are not collecting any identifiable information through the use of Google’s or any other third party remarketing services. However, you can find out more about the data that will be collected by Google and how it will be processed here: How Google uses information from sites or apps that use our services

The third-party vendors, including Google, whose services we use, will place cookies on users’ web browsers to serve ads based on past visits to our website. Third party vendors, including Google, use cookies to serve ads based on a user’s prior visits to our website. This allows us to make special offers and continue to market our services to those who have shown interest in our service.

To use as described above the personal data of users or visitors who are based in EU, we will rely on their consent.

Please rest assured that this site shall only collect personal information that you knowingly and willingly provide by way of surveys, completed membership forms, and emails. It is the intent of this site to use personal information only for the purpose for which it was requested and for any additional uses specifically provided on this site.

It is suggested and highly recommended that you review the privacy policies and statements of any website you choose to use or frequent to better understand how other websites garner, use, and share information they collect.

Use of information collected
DKBmed may collect and may use personal information to assist in the operation of our website and to ensure delivery of the services and Programs you need and request. At times, we may find it necessary to use personally identifiable information to keep you informed of other possible products and/or services that may be available to you from DKBmed. DKBmed may also contact you to complete surveys and/or research questionnaires related to your opinion of current or potential future services that may be offered.

DKBmed does not now, and in no circumstance will in the future, sell, rent, or lease any of our customer lists and/or names to any third parties.

We do not use automated decision-making, including profiling.

Sharing your personal data
We do not share your personal information with others except as indicated within this policy.

We may share your information in the following ways:

With third-party service providers, agents, or contractors who are performing or may perform services on our behalf or to assist us with providing services to you. For example, we may engage third-party providers for hosting and IT services. These service providers may have access to your personal or other information as they provide these functions.

DKBmed may find it beneficial to share specific data with our trusted partners in an effort to conduct statistical analysis, provide you with email and/or postal mail, deliver support, and/or arrange for deliveries to be made. Those third parties shall be strictly prohibited from making use of your personal information, other than to deliver the services you requested, and thus they are required to maintain the strictest confidentiality with regard to all your information.

DKBmed may share your data with accredited providers of content or certification bodies when needed to complete certain certifications. This sharing makes the provider of the certification aware of persons who have completed the activity and process the certification to ensure the user receives proper certification.

DKBmed may disclose your personal information, without prior notice to you, only if required to do so in accordance with applicable laws and/or in a good faith belief that such action is deemed necessary or is required to:

  • Remain in conformance with any decrees, laws, and/or statutes or to comply with any process that may be served on DKBmed, and/or our website;
  • Maintain, safeguard, and/or preserve all the rights and/or property of DKBmed;
  • Perform under demanding conditions in an emergency to safeguard the personal safety of users of DKBmed.com and/or their Programs and/or the general public.

Children under the age of 13
DKBmed does not knowingly collect personally identifiable information from children under age thirteen (13) years without verifiable parental consent. If it is determined that such information has been inadvertently collected on anyone under age thirteen (13), we shall immediately take the necessary steps to ensure that such information is deleted from our system's database. Anyone under age thirteen (13) must seek and obtain a parent’s or guardian’s permission to use this website.

Unsubscribe or opt out
Users and/or visitors to our website have the option to discontinue receiving communication from us for any reason and have the right to discontinue receiving communications by email or newsletters. To discontinue or unsubscribe to our website and/or Programs, please send an email to info@dkbmed.com indicating that you want to unsubscribe. If you want to unsubscribe or opt out from any third-party websites linked on DKBmed.com, you must go to the specific websites to unsubscribe and/or opt out.

Links to other web sites
Our website contains links to affiliate and other websites. DKBmed neither claims nor accepts responsibility for any privacy policies, practices, and/or procedures of other such websites. Therefore, we encourage all users and visitors to be aware when they leave our website and to read the privacy statements of every website that collects personally identifiable information. The aforementioned Privacy Policy Agreement applies only to the information collected by our website.

Security
DKBmed shall endeavor and shall take every precaution to maintain adequate physical, procedural, and technical security with respect to our offices and information storage facilities to prevent any loss, misuse, unauthorized access, disclosure, or modification of the user's personal information under our control.

Transfer of data
Your information may be transferred to and processed by DKBmed in the United States or countries other than your own. If you are a data subject in the European Union and the rules of the General Data Protection Regulation (GDPR) apply, we will make sure that any recipients of your data in countries that do not provide the same standard of protection of your personal data as in the EU and where you may not be able to exercise your rights as data subject, have signed special contracts, such as Standard Contractual Clauses, to make sure your confidentiality is respected.

Email marketing
If you are our subscriber/user, we may use your email address to send you offers for educational courses, educational materials, or promotions that we think might be of interest to you, where these are related or similar to DKBmed services and/or Programs that you are using. Each time we send you such marketing or promotional communication, we will provide you the option to refuse future such emails from DKBmed.

How long we will store your personal data
For the various types of personal data we collect, different retention periods may apply. Generally speaking, we store your data for the period for which you use our services and after for the applicable limitation period for related claims.

Your rights under the EU privacy law, the General Data Protection Regulation (GDPR)
If you are a data subject who is in the European Union and the rules of the GDPR are applicable, you will be entitled to the following rights:

  • Right of access – you have the right to request a copy of the information we hold about you.
  • Right of rectification – you have a right to correct data we hold about you that is inaccurate or incomplete.
  • Right to be forgotten – in certain circumstances you can ask that the data we hold about you be erased from our records.
  • Right to restriction of processing – where certain conditions apply you have a right to restrict processing of your personal data.
  • Right of portability – you have the right to have the data we hold about you transferred to another organization when certain circumstances are met.
  • Right to object – you have the right to object to certain types of processing such as direct marketing.
  • Right to object to automated processing, including profiling – you also have the right not to be subject to the legal effects of automated processing or profiling.
  • You have the right to withdraw your consent for processing of your data where such was given without affecting the lawfulness of processing based on consent before its withdrawal.
  • You have the right to lodge a complaint related to collection or the processing of your personal data with the relevant supervisory authority.

If you want to exercise the above-listed rights (except the right to lodge a complaint before a supervisory authority), or to obtain a copy of the Standard Contractual Clauses, please submit a request to info@dkbmed.com.

Changes to Privacy Policy
DKBmed reserves the right to update and/or change the terms of our Privacy Policy, and we will post those changes to our website privacy page at DKBmed.com and our Program’s Privacy Policy page, so our users and/or visitors are always aware of the type of information we collect, how it will be used, and under what circumstances, if any, we may disclose such information. If at any time DKBmed decides to use any personally identifiable information on file in a manner other than that which was stated when this information was initially collected, the user or users shall be promptly notified by email. Users at that time shall have the option whether or not to permit the use of their information in this separate manner.

Acceptance of terms
Through using this website, you hereby accept the terms and conditions stipulated within the aforementioned Privacy Policy. If you do not agree with our terms and conditions, you should refrain from further use of our sites. In addition, your continued use of our websites following the posting of any updates or changes to our terms and conditions shall mean that you agree with and accept such changes.

How to contact us
If you have any questions or concerns regarding the Privacy Policy related to our website, please feel free to contact us at the following email, telephone number, or mailing addresses:

Email:
info@dkbmed.com

Telephone:
646-336-6495

Mailing address:
DKBmed, LLC
122 W. 26th St., Suite 1100
New York, New York 10001

We want to inform you that we have appointed EU GDPR Privacy Officers Ltd. with email info@privacy-officers.eu, as our data protection representative based in the European Union in order to comply with the requirements of the GDPR.