George Sakoulas, MD, UC San Diego School of Medicine, discusses the issues involved with treating acute bacterial skin and skin structure infections, including compliance, duration of therapy, and areas of unmet need.

Acute bacterial skin and skin structure infections (ABSSSI) can definitely be challenging to treat, in part actually for a good thing, because we have lots of options out there that treat infections and finding the right agent for the particular patient can be a little challenging. Weighing in what particular bacteria can cause the infection, as well as weighing in the patient's immunocompromised or non-immunocompromised state, comorbidities leave open lots of options and choices, and deciding whether to give someone oral antibiotics versus intravenous antibiotics, inpatient versus outpatient, there are a lot of factors that need to be weighed in when making such decisions and treating them.

Areas of unmet need for ABSSSI largely weigh in on pharmaco-economically balancing what's available, getting patients on the therapy that is most efficient, not just in terms of restoring them back to their life, back home, and back to their jobs, taking care of their children and so on…and minimizing stays in the hospital. Studying that and defining in a more black-and-white, more tangible fashion, I think is one of the largest unmet needs when trying to establish data for clinicians to make decisions for treating ABSSSI.

Compliance in patients with ABSSSI, it can definitely be a big problem. Largely because many of the patients are younger, they don't have a lot of medical problems. They don't take their health that seriously. They see the immediate need when they're very ill or when they have the immediate problem, and once their treatment has begun then they forget about it, it becomes less urgent and they're off to the routines of their lives, not worrying about what antibiotics you have to take and how often.

So clearly with that kind of scenario, the less doses a patient requires per day, the better it's going to be. It's a lot easier for someone to remember to take a medication once a day, as opposed to having to take something four times a day. For example, cephalexin, great drug on paper, covers [methicillin-sensitive 

]. Bad news is, how often is someone going to remember to take cephalexin 4 times a day? The options of once-daily dosing, and now we actually have drugs that can be given once in an emergency room setting or outpatient urgent care setting where the patient can be given an IV dose that lasts a week and doesn't have to worry about taking any more doses.

The compliance factor is balanced by the fact that some patients only need 2 or 3 days of antibiotics. They take their course and many of them do fine. Unfortunately, there are some patients who do stop prematurely and they wind up having to come back to the hospital. So you're balancing the, “I'm done, not taking more than I need to take” versus “okay, well, I stopped too early” and then having to continue. So, obviously, if you're worried about compliance, less doses per day and even eliminating the need to take any antibiotics with a parenteral, one-time dose is one of the options we have available today.

Duration of therapy, it’s sort of a black box, not only for ABSSSI, but also for all infections. How long to treat a patient is really almost a case by case basis. We have guidance, 5 to 14 days or 7 to 14 days based on historical paradigms, but at the end of the day, some patients are better with 3 days of treatment and they don't need any more; some patients need longer. One of the variables that determines duration of treatment is the patient’s underlying immunosuppression and comorbidity state. Obviously, if you have a patient with more comorbidities, you're going to need to treat longer. If you have a patient who has a larger burden of infection, you're also going to need to treat longer. So, balancing the immunosuppression and infection burden of a particular patient is a moving target patient to patient, and very difficult to establish. With some clinical judgment, an experienced physician can decide, “Okay, you're a 5-day person versus a 10-day person” and hopefully make the right decisions and hopefully the patient can comply with that recommendation to minimize the relapses.

Unfortunately, one of the problems we also have with this situation is with 

 frequently, you could treat them, they get through the acute period, but the mere colonization opens up an opportunity for another infection to happen. Not an issue of compliance or you didn't give them enough therapy, but the fact that they're colonized sets up an opportunity for a recurrent, not necessarily a relapse infection, but a recurrent infection a few weeks later and we in practice, see that all the time.

IDWeek 2019 News Network: The Challenges of Treating ABSSSI

George Sakoulas, MD, UC San Diego School of Medicine, discusses the issues involved with treating acute bacterial skin and skin structure infections, including cutting down on readmission rates and how site of care affects treatment costs.

With [acute bacterial skin and skin structure infections (ABSSSI)], readmission rates are a big problem, largely driven by the fact that a lot of ABSSSI is caused by [

] colonization, particularly some of these community acquired MRSA strains that have virulence factors that mediate, reinfection can be a problem. So in other words, you've done all the right things, you treated the patient with their appropriate duration of treatment, but then by merely the fact that they’re colonized, they, get another infection at a different location within a week, or a month, or a couple of months. We see these patients all the time.

First, recognizing the possibility this could be 

colonization, you know, with second, third occurrence, you implement not just a treatment program for that particular infection, but perhaps also a decolonization paradigm keeping in mind things like washing with chlorhexidine, either daily or several times a week, bleach baths for a few weeks after infection to see if that is enough to break the cycle of reinfection. Other options that we've done for patients is taken the paradigm of how dermatologists treat acne, where tetracyclines are given for a prolonged period of time. So we sometimes will give patients minocycline for a month and hopefully that gives us a durable decolonization and a durable response, Mupirocin is another decolonizing agent.

So those types of things: keeping in mind that [

] colonization and addressing the colonization factor is an important aspect of preventing recurrences and keeping in mind that fomites at home, other family members, even family pets can be reservoirs for recolonization and then keeping that in mind. Even if you go through a particular decolonization for a patient, recognizing the fact that you may have to take it into the immediate family household.

The site of care obviously has an impact on resources used and cost in treating ABSSSI. A patient comes to the emergency room, then there's a possibility that they're going to get admitted, when they get admitted to the hospital, chances are, they may get an antibiotic, vancomycin is one example, that is very cheap in and of itself, but by virtue of its very slow activity, and its overall poor anti-

 activity makes the patient better but it takes a while to do so. And so once you've crossed that barrier into admitting someone to the hospital from an emergency room setting, that sets up a hospitalization frequently four or five days long, using medications that are cheap to acquire, but slowly act, it then leads to hospital stays that perhaps could be shortened up by using alternative agents that are faster.

Sometimes if you can avoid patients going to the hospital for the emergency room, you can get diverted with either an oral agent if they're not that ill, or perhaps one of those one-time doses like dalbavancin that can be dosed once and outpatient, it's an investment in drug cost up-front but at the end of the day might be overall cheaper than a 5 to 6  day hospitalization to get a drug like vancomycin. So, cost of care again, that's one of the challenges in treating ABSSSI. What you don't like seeing happening is what I see sometimes in urgent care settings where physicians will see a patient having to come back and get a medication like vancomycin once daily, or some other medication that is sub-optimally dosed, just to go back and forth from an urgent care setting to avoid the hospital stay. Many times those things backfire and the patient winds up just lingering and not getting better, ultimately admitted, and it just adds to the prolonged care of that patient.

IDWeek 2019 News Network: How to Cut Down on ABSSSI Readmission Rates

George Sakoulas, MD, UC San Diego School of Medicine, discusses the current treatment landscape for community acquired bacterial pneumonia and comments on new guidelines for treatment.

Some of our newer agents, omadacycline and delafloxacin, have obtained almost simultaneous approvals or simultaneous approvals for both ABSSSI and community acquired bacterial pneumonia (CABP). That speaks to 2 things…1) the illnesses are largely driven by gram-positive agents. So in skin infections, you have 

, either group A or group B or other beta-hemolytic 

. In community acquired bacterial pneumonia, again, it’s a 

. Gram-negatives take on a more important role in both of those illnesses as the patient becomes more comorbid, more immunocompromised, and so they have relatively similar spectra to cover: 

 in both settings. Skin, pneumonia, and UTI are the 3 most common infections that we see in hospitals. And so getting drugs through the approval process through registration trials, it's easier to go for infections that are very easy to enroll in, ie, common ones like pneumonia and skin, in order to get a drug onto the marketplace rather than starting with an illness that might actually have a larger medical need for newer antibiotics but would be harder to enroll patients in, like bacteremias or osteomyelitis and so on. And so hence the very similar crossover and simultaneous approval for drugs with community acquired bacterial pneumonia and ABSSSI.

Community acquired bacterial pneumonia is an interesting entity at the moment. We have lots of agents available. Traditionally, we've had fluoroquinolones that have essentially been the cornerstone of that market. But there's been recent concerns with fluoroquinolones, concerns of glycemic control, QT prolongation, [

 concerns, tendon ruptures, now aortic ruptures. In fact, the FDA has actually taken a few steps to issue warnings, most recently with aortic rupture warnings back last December, really leaving physicians who are prescribing fluoroquinolones and patients with community acquired bacterial pneumonias and comorbidities balancing these dark clouds hanging in the distance, hoping that the patient doesn't have any complications. And the one that really comes to mind in real time is 

 is clearly a risk with fluoroquinolone use. Elderly patients are the ones that get pneumonia, they're also the ones at highest risk for forgetting 

 So I think the most difficult dilemma that clinicians are faced when treating pneumonia, you want to try to use a, perhaps a non-quinolone, because you don't want to go through the risk that I just mentioned, but at the same time you don't want to miss the pathogen by using a drug like tetracycline that doesn’t have really good pneumococcal activity. So that that really is the sort of dilemma facing physicians, particularly in an outpatient setting, or when you're discharging a patient home after a short hospital stay for pneumonia in selecting therapy.

The new guidelines for CABP were recently released within the last few days. I looked them over and there's been some updates with them. There are comments on procalcitonin, which we're not on the old guidelines because the old guidelines were issued before procalcitonin, when it became a mainstream option for clinicians, and the comment about not using it to decide whether a patient needs or does not need antibiotics. I think an important point in there that was highlighted was the use of sequential radiographs. A lot of clinicians chase follow up X-rays that wind up getting them into trouble, perhaps overtreating because patients have already graphic lag so issuing recommendations for not getting follow up chest X-rays which might have been a traditional practice for many physicians, I think is a very positive aspects. The use of glucocorticoids also was argued against in most cases except severe sepsis.

What was a little bit disappointing was the lack of mention of the new agents and the role they might have played like omadacycline, delafloxacin, the pleuromutilin lefamulin. And they were all recently approved options that clinicians have and they were completely left off the treatment guidelines. I think clinicians when facing these guidelines and looking at these guidelines might need some guidance and incorporating these and it would have been nice if these guidelines address that, how they would be incorporated, for example, balancing the risk of 

 with quinolones, and which high risk patients might benefit from some these newer agents despite their higher costs, so that was lacking, I think it speaks to the long process that leads to guidelines being ultimately published, probably one of the reasons why many of us don't refer to textbooks anymore because textbooks, by the time they get written up and put in print, they're outdated. And it almost appears that the guidelines sort of fell victim to that kind of process as well. It's the long cumbersome process of getting them to print kind of left them missing out on the new developments and clinicians’ guidance, so, hopefully it won't be too long before the new agents are addressed in that decision process.

IDWeek 2019 News Network: Current Treatment Landscape for Pneumonia

 Joseph Reilly, BS, PharmD, BCGP, Clinical Pharmacist, Atlanticare Regional Medical Center, discusses the current treatment landscape for ABSSSI and areas of unmet need.

Interview transcript: (modified slightly for readability) 

I think there's a number of treatments available that are effective for skin infections and they cover the typical pathogens we would expect to encounter gram-positive cocci, including methicillin-resistant 

. The major issue that comes to mind is ensuring that a patient will take a full course of therapy because of compliance and transition from the inpatient to the outpatient setting.

 [Patient compliance] certainly is an issue to consider for providers. How would we make sure that patients are going to take full course of antibiotics? Because we want them to take their full course. Hospitals certainly don't want the readmissions. And we don't want disease progression. So the skin infection can turn into a bacteremia or an osteo or an endocarditis for that matter. How they can do it, there's not really an option for direct observed care where they're going to watch patients take antibiotics. There are some new therapies out there, long-acting lipoglycopeptides, where a single dose would ensure you know, 10 plus days of IV antibiotics, and that way we can remove the compliance issue from the patients. So that's certainly an option for patients that present with skin infections, and you could prevent admissions with that. And it's also an option for patients that are admitted to a hospital that have a skin infection, and now they're going to be discharged on oral antibiotics.

I mean, our biggest concern in a hospital is when we discharged somebody with a skin infection. We want to make sure that they take their oral antibiotics and the outpatient setting and from what we know looking at our numbers, that doesn't always happen.

IDWeek2019 News Network: Urgent Areas of Unmet Need in ABSSSI

Joseph Reilly, BS, PharmD, BCGP, Clinical Pharmacist, Atlanticare Regional Medical Center, discusses duration of therapy and preventing readmission for ABSSSIs.

When patients are admitted with skin infections, a lot of times we will give them IV vancomycin, and after a certain number of days, hopefully, it's under 4, we want to transition that patient to the outpatient setting. Now the question is, what's the best available option? We have to consider, why was the patient admitted in the first place, and many times we've learned from examining these patients that are admitted, they're often admitted and they're hemodynamically stable, providers encountered this patient in an urgent care setting or in the ED just decided that this patient is not a  candidate for oral antibiotics because of compliance. So when patients stay four or five days in a hospital with a skin infection, if they're hospitalized because of it, they should probably have at least 10 days of antibiotics. What we often do with these patients, we’ll put them on oral antibiotics and discharge them, we found that our readmission rate is high, often 15%, they come back within 30 days with their skin infection, again, the same one. We also discharge patients and we give them oritavancin, a long-acting lipoglycopeptide, and send them on their way. And what we found is they don't often come back, it's actually less than 3% readmission rates. So the key really is compliance: can we ensure that these patients are going to finish their course of microbial therapy? And it's best for them to prevent disease progression, prevent readmissions that of course, are expensive for a hospital.

The readmissions are certainly a concern. And depending on your population, we've seen in studies readmission rates within 30 days anywhere from 10 to 20%. At our institution, it's 10 to 20%, just for skin infections, or something related to their skin infection. And once again, it just goes back to compliance. Who are these patients being admitted to the hospital? Why did they come to the end with their skin infection, and how can we prevent them from coming back and having a prolonged length of stay and complications associated with being hospitalized? and the long-acting lipoglycopeptides, we have utilized oritavancin in this patient population, and despite the initial acquisition cost, which will impact a pharmacy budget, what we found is that it's economically beneficial for a hospital to use these more expensive drugs initially, because they wind up saving money for the hospital in a significant fashion.

So we can prevent readmissions. Every time somebody is admitted at our institution with a skin infection, we lose somewhere about 4 to $8000 per case. So when we use oritavancin in this patient population, what we find is, it has an initial cost that's higher than standard therapies, we can get reimbursed for the drug, and we have a lower readmission rate and we have a shorter duration of hospitalization.

IDWeek2019 News Network: Preventing Readmissions for ABSSSI

 Thomas Lodise, PharmD, PhD, professor, Albany College of Pharmacy, provides an overview of new agents for treating CABP and discusses reducing the costs of treatment.

Interview transcript: (modified slightly for readability)

The question becomes how can we reduce the overall cost? I think that kind of is a good segue with my previous response, and I think we need to be more acutely aware when we standardize our mission practices for patients who presented to the ED with community-acquired bacterial pneumonia (CABP), with suspected or documented CABP. It should be taken into account if there's an opportunity to treat the patient briefly in the observation unit that should be preferred over a short hospital admission.

On the flip side of that is among our admitted patients, what we're finding is there's a number of studies—largely generated outside the United States&mdash;is a lot of patients with infections stay in a hospital, past infection resolution. I think a lot of times the patients start on IV antibiotic, even though their infection resolves and they're improving… I wouldn't say they're back to their baseline but they're improving, and they tend to stay in a hospital longer than probably necessary.

If one considers each day of hospitalization for a CABP patient is $2500 even a 1- or 2-day hospital stay reduction could have a substantial impact on the overall cost of care. So really, I think it's really 2-fold. Better triaging patients who present to the emergency department, admitting patients who need to be admitted, and for our admitted patients, you know, when their infections resolve and there’s an opportunity to discharge to home, to do so. And this is usually 24 hours after they have clinical stabilization and improvement in some of their symptoms.

As I mentioned before we only have a limited number of classes available for CABP. We have our β-lactams or penicillin and cephalosporins. We have our respiratory fluoroquinolones which are levofloxacin and moxifloxacin. We have macrolides which we can only use in combination, as well as doxycycline. So beyond them, we had 2 drugs recently approved. Lefamulin, which is a pleuromutilin antibiotic [that is] available both intravenous and oral, was recently indicated for the treatment of adults with CABP. Also, we have omadacycline, which is a next-generation tetracycline type antibiotic, which is indicated for both patients with acute bacterial skin and skin structure infections, as well as adults with CABP. Similar to lefamulin, omadacycline is available both intravenous and oral, but for patients with CABP, intravenous [administration] should be started because this was the practice within its clinical trials. So right now, they have no oral-only data among patients with CABP with omadacycline.

IDWeek 2019 News Network: Reducing Cost for CABP and Exploring New Agents

 Thomas Lodise, PharmD, PhD, professor, Albany College of Pharmacy, shares his initial reactions to the updated CAP guidelines.

. They only became available this week, so I haven't been able to do a very deep dive. My overall impression is, this is largely consistent with the previous guidelines. They still stratify patients, either outpatient or inpatient. In the outpatient setting, they provide treatment recommendations in the presence of or absence of comorbid conditions like heart failure, renal disease, and things of that nature. And then for the inpatient setting, they stratify patients by hospital ward versus the ICU [intensive care unit], and the ICU is your typical ICU patient patients, septic sepsis or septic shock.

Across those different stratifications, there are a few differences. First, as I mentioned before, macrolides should not be used in monotherapy with regions greater than 25% macrolide resistance in 

, which is the No. 1 cause of CABP. Unfortunately, we don’t have a lot of good surveillance data, with 

 in different regions. And when we do look at it, most regions have 40%.

So really the guidelines indicate that macrolides should not be used alone, which is a new recommendation and contrasted to [the 2007 guidelines]. For patients with comorbidities, they recommend using β-lactams or fluoroquinolones. However, they make mention of some of the concerns with the fluoroquinolones within the guidelines. There's been a number of boxed warnings over the past few years. In years past we had issues with QTC prolongation, tendinitis and tendon rupture. More recently, the most recent update is the increased risk of aortic aneurysm, particularly among patients with cardiac risk factors.

I think from that standpoint, we have a few different iterations. But largely the treatment choices are the same. Inpatient, it's still a beta-lactam with the macrolides or respiratory fluoroquinolones for your hospital ward patients. And for our critically ill patients in the ICU, it’s a β-lactam with a macrolide or a β-lactam with a fluoroquinolone. They do discuss that there appears to be some advantage in our ICU patients using a β-lactam with a macrolide over with a fluoroquinolone. However, they said either one is an acceptable recommendation.

Another big difference with the guidelines is the whole idea of HCAP. So actually HCAP is health care-associated pneumonia. This was from the previous ATS IDSA [American Thoracic Society and Infectious Diseases Society of America] pneumonia guidelines. So they make mention of this and said that this designation should be avoided. And rather what they added is the treatment of community-acquired pneumonia and patients at risk for MRSA or 

. So, what they did in this circumstance with someone who's at risk, prior 

 or MRSA infection, or was colonized with MRSA or 

, those individuals should be empirically treated if they're in septic shock, or if they have a positive culture at presentation among our hospital ward patients. So this is a recommendation primarily for your inpatients. Because if patients do have risk factors for MRSA or 

, those are the ones that tend to be admitted who have high acute disease severity.

Interestingly, for our hospital ward patients, they indicated to only add MRSA or 

 coverage if the pathogen is identified. For MRSA, it could be PCR for 

 on a clinical culture or the patient has history of MRSA or 

infection. In that circumstance, if MRSA is previously recovered, to use vancomycin or linezolid, if Pseudomonas was previously identified, then consider an anti-Pseudomonal β-lactam.

And then again, those in septic shock, [the committee] recommend to use those drugs empirically and de-escalate if they’re not recovered. So I think these are some of the biggest differences, you know, still largely the same, but they did provide greater clarity on that HCAP designation which we all struggle with. They do mention about patients at risk for MRSA, within a hospital, the risk of MRSA should be predicated on some validated institution-specific clinical prediction rules, they acknowledge those are not readily available. So this is something that will need further clarification as we move forward in practice.

I think the biggest thing is that if they had MRSA in the past, you should probably cover MRSA. 

. If you have it on culture, personally, I think I would probably cover them empirically and in a high-risk patient, perhaps coming from a nursing home, or as a health care frequent flyer with a lot of prior antibiotic exposures. However, this recommendation that’s made is in conflict for patients who are sick with pneumonia admitted but not treated within the ICU. So these are the patients without severe pneumonia.

IDWeek 2019 News Network: Initial Reactions to Updated CAP Guidelines

 Thomas Lodise, PharmD, PhD, professor, Albany College of Pharmacy, reviews the 2019 CAP guidelines and highlights areas that could be improved in future updates.

The question is, how can the guidelines be improved? I’ve served on guidelines committees. It’s challenging, you have to rely on available evidence to make decisions within certain criteria.

I appreciate them maintaining a current stratification. I think this is something we're all familiar with, and thinking about outpatients, whether or not they have comorbidities, and treatment selection, whether they're in the inpatient ward or within the ICU, and providing some guidance on how to handle patients at risk for MRSA and 

So I think their overall structure and stratification really provides a good framework for identifying what drugs could potentially be considered for your patient and also to provide some clarity even though they may not make a strong recommendation of one recommendation over another, because they usually give a few options some of the guiding evidence and principles which may lead you to take one drug combination over another for example, in patients within the ICU.

I appreciate the move away from HCAP, and, to streamline clinicians to check prior culture data. Given the importance of getting it right the first time, I wish they were a bit more aggressive. They do recommend empirically covering MRSA and 

 in patients with risk factors for those if they have severe pneumonia, which is basically pneumonia in septic shock. However, my fear is we may undertreat a few patients who could potentially progress to septic shock. I think their recommendation for this was based on the best available evidence showing that we overtreat drug-resistant pathogens. But I still think we have to have a bit more in a bit more work in that area, because there's a recommendation to rely on institute validated risk factor scores. And this is something that a lot of institutions do not have.

So I do think there's an opportunity to better clarify who is our CABP patients at risk for MRSA, pneumonia and 

 pneumonia, more than just having it on a prior culture or current culture or PCR nares test. The other thing I think they could have done is provided a bit more clarity on the role of new drugs. As I mentioned before we have lefamulin and omadacycline. Omadacycline is mentioned twice in the document lefamulin is mentioned once and both in the future research direction section, citing limited experience.

Why this is true? These 2 agents have gone through recent FDA guidance for approval. There’s a focus on patient-reported outcomes, symptomatic improvement. So these are all things that are of value and they moved away from a lot of test to cure assessment, which was a clinician assessment of the patient's response.

Lefamulin has 2 phase 3 clinical trials and omadacycline has 1. So I think we could add defining their roles in therapy, perhaps not as first-line therapy but for patients at high risk for a fluoroquinolone associated adverse event. If you just look at the packet insert of the fluoroquinolones, there's a lot of class effects listed, you know, aortic aneurysm, patients over 65 [years of age], cardiac conditions, hypertension, patients with renal failure; these are all at increased risk of certain adverse events associated with fluoroquinolones.

So I think there was an opportunity there within the guidelines to better perhaps define the use of our newer drugs in those patients. Alternatively, they can say in those patients, maybe there should be preferential use of a β-lactam with a macrolide. I think these are opportunities, but recognizing that the guideline committee relies on best available agents and with the newer agents, you only have phase 3 clinical data, 2 clinical trials with lefamulin, 1 with omadacycline.

So I appreciate the need for further data, but I think in clinical practices we have these fluoroquinolones which are our go-to CABP drugs, they have tremendous efficacy, you'll never have a more efficacious drug class than fluoroquinolones in patients with CABP; however, from our federal government—and this is also with the EU as well&mdash;they identify a number of serious adverse events.

Looking at overall fluoroquinolones use, these adverse events are low, but they do identify some high-risk patient populations. So in the next iteration of the guidelines now it's taken us 12 years to get this one. When will this occur? I do not know. But I think all clinicians would benefit from better clarity on what drugs we should use in patient populations at high risk for fluoroquinolone adverse events, given that they have historically been one of our go-to agents for patients with community-acquired bacterial pneumonia.

IDWeek 2019 News Network: Advances in Treating and Managing ABSSSI and Community Acquired Pneumonia