Warren S Joseph, DPM discusses the current treatment guidelines for MRSA. Dr Joseph presents clinical data to question how we are doing in the fight against MRSA and if treatment is even necessary. He also discusses newer treatment options available and if these medications are viable options in our hospitals.
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Warren Joseph, DPM
Roxborough Memorial Hospital
Editor - Journal of the APMA
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Warren Joseph Warren S Joseph, DPM, FIDSA has disclosed that he receives Honorarium/Expenses, is a Consultant to and serves on the Speaker's Bureau for Pfizer and Merck.
Male Speaker: A lot of you referred number of my different lectures over the years both here on present and various meetings around the country. Well I’m here to promise you I have something new for you. This is a brand new lecture. You weren’t have heard this one before anywhere. I just came up with this the other day just finished it up. So this is almost going to be a trial run. So I have to excuse myself right off the bat in case this is not quite as smooth maybe as you might be used to hearing me give these talks. But what we’re going to do is we’re going to talk about what’s new to treat MRSA? Now just to give you some disclosures, I am a member of the Speakers Guild of Cuba’s Pharmaceuticals even though at the time of this filming, I’ve done a lot of one talk for them. And I do received research support from them. And I am a consultant to Dipexium Pharmaceuticals who make pexiganan, we’re going to talk about that in the lecture. So these are the only two disclosures I currently have for any lecture on MRSA. Well what are we going to cover in this talk? Do we even need to concern ourselves? Wow, that’s a pretty deep thought when you think about it because after all, we’ve all heard so much about MRSA over the years. And there’s so much press coverage of MRSA. Well do you really need to be concerned about it? There’s been a decrease in patients presenting with MRSA. I’m going to show you that data. And even if MRSA is present, some evidence shows it may not really make a difference in the outcomes for the patient. We have lots of treatments from MRSA in particular vancomycin probably being the most common. Well what’s wrong with the treatments we have now? Why do we even need new treatments for MRSA? There’ve been changes in the FDA’s guidance for industry in the approval of antibiotics for skin and skin structure infection. That really makes some difference in how antibiotics are approved and one antibiotics are approved and what the labeling says. We’re going to talk about that a little bit. Interestingly, there’ve been a number of new antibiotics approved since Ceftaroline was approve in 2012. So because of some of these changes in FDA guidance and because of the issues such as the GAIN Act which is the new antibiotic incentive act which gives [pan] [02:37] protection to companies for a longer periods of time to developing antibiotics. And something called the QIDP or Qualifying Infectious Disease Product legislation, we have now incentive for the first time for pharmaceutical companies to develop new antibiotics. And you’re seeing that happen in all the work lately has been in MRSA. And then what’s in the pipeline? Because the pipeline for MRSA is pretty deep. We’ll talk about that also. Well let’s start with the first question. Do we still need to be concerned about MRSA? This is a paper that was published and looked at healthcare associated invasive MRSA infections between 2005 and 2008. Now this was in Journal of American Medical Association. They concluded that over the four year period from 2005 to 2008, benign diverse metropolitan areas, the rates of invasive healthcare associated MRSA infections decreased among patients with healthcare associated infections that began in the community. So this MRSA epidemics started around 1997-1998, that’s when we first started looking at healthcare associative versus community acquired MRSA. Well now it’s dying out a little bit. You can see that after 2008. Well 2008 is a number of years ago, there’s actually a more recent reference that I found in JAMA Internal Medicine. They look at national burden of invasive methicillin-resistant staph infections in United States through 2011. And this was just published in 2013. And what you can see is these blue bars represent rates of MRSA and you can see from 2005 right through to 2011, in all categories of MRSA there has been a decrease in the number of patients we see with that. Now how we attribute this? What is the reason for this? Well certainly the infection preventionist will tell you that it is all of the good infection control and prevention measures being taken and all of the alcohol you see everywhere in every store and every hospital, every hotel.
Maybe that’s it, but I think some of these are just because these infections are cyclical. One year you’ll read a lot about bird flu. One year you’ll read a lot about SARS then in the next year you won’t hear anything about it. Well same thing with MRSA. MRSA became big back in the late 1990s now, maybe it’s dying out a little bit. So we know the numbers of MRSA have decreased but what happens if the patient does come in with MRSA? Does it make a difference? Do they have different outcomes? Well this is a paper out of University of Geneva, Dr. Ben Lipsky was worked on this with a number of his colleagues out in Geneva. And this was specifically looking at diabetic foot infections with MRSA. And that the outcomes differ versus those of other pathogens. This is right from the manuscript. What it says is our review of literature with the other many studies have been published, the report on patients with diabetic foot infections caused by MRSA. Unfortunately, the published studies provide no robust clinical data to inform either diabetic foot caused by MRSA associated with different clinical presentations or outcomes compared to those by other pathogens. So even if the patient does have MRSA, you treat it. It doesn’t mean that the patient’s going to necessarily do any worse. Certainly, you listen to the popular press and you hear about flesh eating bacteria and superbugs and I can’t tell you the number of organisms that have been called superbugs over the years. MRSA being one of the big ones. But maybe when it’s really treated it doesn’t make a difference and the outcomes are not going to be any different or any more super than with any other organism. So this is again right from the paper and what they do is they talked about some of the treatment regimens from MRSA. Certainly they look at skin and skin structure infections that are mild, talk about oral therapy with Clindamycin, Trimethoprim, Sulfamethoxazole or maybe Doxycycline which is my favorite. The Nasalide, the new drug Tedizolid any number that could be used for this. But then I talked about the moderate or severe and they’re looking about Vancomycin and Trough levels I want to come back to the slide a little bit later when we talk specifically about Vancomycin and some of the problems associated with it. But other drugs you can use, Actinomycin, Tetracycline again Linezolid, Tedizolid and any of the other new drugs we’re going to be talking about could be used for this moderate to severe infections. But keep that in mind because we need to discuss Vancomycin and how we dose it. Well what’s been out there in the MRSA world? Certainly from mild infections, we’ve had the later generation Tetracyclines such as Doxycycline and Minocycline. We’ve had Trimethoprim sulfa, Clindamycin which yes you may be able to use especially if the patient is what we called D-test negative. I’ve just looked at the erythromycin line, if the erythromycin line says resistant, gets cross resistant between erythromycin and Clindamycin, I wouldn’t consider Clindamycin in those cases. And then there’s the potential to either positively or negatively or plus or minus Rifampicin or Rifampin to any of these regimens. I don’t use a lot of Rifampins certainly more of it been used in Europe and in other parts I think for things such as osteomyelitis. It might be wise if you’re using Minocycline or Doxycycline or Trimethoprim sulfa to consider adding Rifampin to those cases. But that’s what we’ve had out there. Now I will tell you that none of these drugs are actually officially FDA approved for the treatment of MRSA. They’ve just been shown to be effective against MRSA. Well, we do have five FDA approved drugs for the treatment of acute bacterial or complicated bacterial skin and skin structure infections caused by MRSA. Now they include Linezolid, Vancomycin, Daptomycin, Tigecycline and Ceftaroline. Again, that’s to about 2010 we had these drugs. We’re going to talk about some of the newer drugs later on this talk. To me, however, one of the most important ways you can control MRSA is right here. And maybe this is why those MRSA rates are decreasing maybe the infection preventionist do have something or they are onto something. This was a one-page article that was published in the New England Journal of Medicine a couple of years ago. Well they just had a healthcare worker performing abdominal examination on a patient who was galvanized with MRSA. They then had a healthcare worker come out and put his hand on this agar plate. And you can see almost that perfect hand print of MRSA. Well then they had the healthcare worker go back in and he do the examination again.
But this time come out and used proper hand sanitization, proper hand disinfection. And you can see after putting his hand on the plate, there was no MRSA found. I think the number one way to control MRSA is proper hand hygiene whether it be handwashing or whether it be alcohol-based hand rubs. I think this is how we keep MRSA rates down and keep them declining. Well of the drugs that have been out there so far, they’re fairly effective. This is an interesting paper that was published just last year in Journal of Antimicrobial Chemotherapy which looked at a randomized non-inferiority trial comparing Trimethoprim sulfa plus Rifampicin. So I mentioned that before, the potential addition of that versus Linezolid which is usually reserved for more severe infection, it’s a newer drug for the treatment of MRSA infection. And what do you see of the circled areas here, it’s for skin and skin structure infection success rates were 76.2% for Linezolid versus 83.3% for the Trimethoprim sulfa plus the Rifampicin. So maybe going back and even use in these older less expensive drugs can still be effective in the treatment of MRSA. Well what about Vancomycin? Every hospital, everywhere you go, every patient gets put on Vancomycin. Some hospitals have taken and calling Vitamin V because every patient comes in the Emergency Department gets a grammar to a Vancomycin being hand. Well this is an interesting point counterpoint, we took part at the Infectious Disease Society of American Meeting a number of years ago. And they then took their point and counter point and rolled it up for clinical infectious diseases. And the counterpoint was done by Dr. Stryjewski out of Stanford. And what Dr. Stryjewski found in his counter point entitled Vancomycin and Staphylococcus aureus: An Antibiotic Enters Obsolescence. I love that title. Is he says that the efficacy of Vancomycin for the treatment of patients with infections due to Staph aureus is impaired by its poor tissue penetration and by it’s relatively weak and bacterial activity. An activity is declining as Staph aureus evolves and neither dose escalation nor use of Vancomycin in combination with other antibiotics had been shown to safely enhance the therapeutic efficacy. That’s a pretty deep statement. We’re using an incredible amount of Vancomycin on patients. That is not a particularly good drug. It’s an old drug. This drug was discovered back in the 1950s. Now it doesn’t mean it won’t work in a good number of patients but its efficacy is decreasing as Staph aureus evolves. Let’s go back to the paper that Dr. Lipsky was part of in the University of Geneva group. What they recommend Vancomycin from moderate to severe infections in diabetic feet and keeping a Trough level of between 15 and 20. Well this is something that’s been all the way germ pharmacy world nowadays. What they do as I say you need to significantly increase the dose of Vancomycin. You need to obtain something called Aucmic ratio of greater than 400. Now, that’s all based on pharmacokinetic, pharmacodynamics modeling. But I will tell you that there is little clinical evidence to base these increased level of Vancomycin, this increased dose of Vancomycin having any greater efficacy in the treatment of skin and soft tissue infections. In fact where there is good evidence, is that by increasing the trough levels to 15 and 20, there are significantly higher rates of acute renal failure. I’ve actually seen it in our hospital. Our hospital, the lab just changed about a year or so ago, changed the trough level target on the lab set to be between 15 and 20. I don’t know what input they got on that but I have a real issue with keeping troughs that high. Now this is based on a guideline that was published by the Infectious Disease Society of America and the American Society of Health System Pharmacist. And part of this, then came out in the clinical practice guideline by the IDSA on the treatment of MRSA infections. You can find this at idsociety.org along with all of the other guidelines clinical practice guidelines put out by the IDSA. And what they did is joined guideline between ASHSP and IDSA, they come out and say, “For serious infections such as bacteremia, infective endocarditis, osteomyelitis, meningitis, pneumonia and severe skin and soft tissue infections such as necrotizing fasciitis.
Due to MRSA, Vancomycin trough concentrations should be kept at 15 to 20. Again, I will tell you that is not based on any human evidence. The only clinical evidence out there is on pneumonias and bacteremias. Also other issues with osteomyelitis being categorized as the same in the same sense as endocarditis or meningitis or pneumonia. Yes, it’s a severe infection. It’s a serious infection. But I certainly don’t consider it in the same category as some of those others in which they’re recommending troughs of 15 to 20. Well, people just go on to this recommendation. We need to keep troughs of 15 to 20. Well they actually read further into the guideline, in fact, you need to read very much further it’s just the [indecipherable] [15:53] recommendation number 64, from most patients with skin and soft tissue infections who had normal renal function and are not obese, traditional dosage of 1 gram every 12 hours are adequate and trough monitoring is not required. Think about that. So they actually came out and said for most skin and soft tissue infections, it’s okay to use 1 gram q 12. And you don’t have to keep troughs of 15 to 20. I have a major problem and there are some pharmacists out there that I have almost gotten into [indecipherable] [16:26] over this need or this push to keep these troughs that high. Because I just think you’re asking for trouble and blowing out patient’s kidneys. Now, I will tell you that we’re going to talk about some of the new drugs for MRSA. None of these drugs are approved for diabetic foot infections. But why is that? Well this is your FDA at work. Because about four or five years ago, the FDA changed the classification and changed the way antibiotics for skin and soft tissue infections are approved. They used to be approved something under something called the complicated skin and skin structure infection guidance. And with that guidance, you could use diabetic foot infection. You can include diabetic foot infection. You can get an indication for diabetic foot infection. Under the new what’s called acute bacterial skin and skin structure infection guidance which the most recent guidance came out is recent as October of 2013. They specifically exclude diabetic foot infection. In fact, this is a quote right from the guidance that says the guidance does not address infections need more complex treatment regimens such as infections resulting from animal or human bite, necrotizing fasciitis, diabetic foot infections, decubitus ulcer infections, myonecrosis, and ecthyma gangrenosum. Sponsors interested in development of drugs for treatment of skin infections not covered in this guidance including diabetic foot infection should discuss clinical development with the FDA. I highlighted those areas. Why? Because think about this. What they’re saying is we don’t believe that antibiotics necessarily have an effect in diabetic foot. We feel that diabetics are more complicated than some other skin and soft tissue infections, therefore if you want to get a diabetic foot indication you have to come talk to us. Well that’s a long expensive process and this is one of the reasons why we’re not saying a lot of new drugs being a looked at for diabetic foot. So what do they base this whole idea of acute bacterial skin and skin structure infection? Well they actually base the guidance on this paper. Look at the date December 11, 1937. This was a paper by Dr. Snodgrass who looked at the use of sulfonamides in the treatment of erisypelas of the face, so basically cellulitis of the face. And I love some of the incumbent therapies that were used with this drug. Patients were either given sulfonamide or not, and you could see under point C there on the right. During the second of any subsequent week, ordinary diet is resumed for example you could have mints, you could have stew, you could have vegetables such as potatoes, cabbage and turnips, steamed puddings. This is the state of the art in 1937. Yet this is now that the FDA is using to base their new guidance. Think a one step further than that, Snodgrass actually went as far as saying on admission, each patient was given a soap and water enema repeated when necessary. They’re after the same laxative, liquid paraffin was used. To me, it’s a little bit difficult to believe that new antibiotics in 2015 are being approved based on guidance developed from – if you want to call this study a study performed in 1937. But this is the reason why, we don’t have diabetic foot infection in the new drugs. So let’s just finish up talking about some of the new antibiotics that are out there.
Tedizolid or Sivextro this was FDA approved in June of all of this past year. As you can tell it’s an oxazolidinone by the name Tedizolid very similar to Linezolid. Unlike Linezolid which was 600 milligrams twice a day for 10 days, the clinical trials on Tedizolid were 200 milligrams once daily either IV or p.o. for six days. It was found in the clinical trials be non-inferior to Linezolid twice a day for that 10-day course of therapy. Unlike Linezolid, there are no SSRI or serotonin syndrome precautions. Remember that was a big issue when you wanted to use Linezolid on a patient on SSRI, did everyone was concerned about serotonin syndrome. That precaution does not exist in this drug. Myelosuppression was about half of that including thrombocytopenia, about half of that of Linezolid. And the drug is effective against MRSA, VRE, Vanco and Dapto resistant Staph aureus. And because it’s once a day and it’s only six days versus 10 days, it comes in at a lower cost than Linezolid. And that always was an issue trying to use Linezolid. Now, Cuba’s did two clinical trials. They called them the established one and two studies, established one IV only established two is IV switching over to p.o. and they looked at all skin and skin structure infections. This particular paper on Antimicrobial Agents and Chemotherapy by Andy Shore is just looking at the pulled data from those two clinical trials. And what they did again is they did Linezolid 600 twice a day versus Tedizolid 200 once a day. And you can see for Staph aureus including MRSA 85.1% early clinical response rate for Linezolid 80.7 early clinical response rate. So the 200 milligrams once a day for six days was not inferior to the Linezolid 600 milligrams twice a day for 10 days. As for myelosuppression, you can see in the white bars Tedizolid and the black bar – excuse me the white bar is Linezolid and the black bar is Tedizolid. You can see there was about half of the myelosuppression you see with Linezolid. So that’s Tedizolid. Then we have three antibiotics that fall under the category of lipoglycopeptides. They’re actually somewhat related to Vancomycin. Televancin or Vibrativ is a lipoglycopeptide first FDA approved in 2013 for the treatment of complicated skin and skin structure infections. It worked against MRSA and VRE. Most common effects because it is related to Vancomycin, you have taste disturbance, nausea and vomiting and foamy urine. Rapid infusion can result in retina syndrome so it has to be infused over 16 minute period of time. Personally, I haven’t found a lot of reason or a lot of justification to start using Televancin for skin and skin structure infections at this point. These two newer drugs though I find somewhat interesting, both the Oritavancin and the Dalbavancin. Now Oritavancin was FDA approved in August of this past year and their phase III solo program, they looked at a single 1,200 milligram dose of Oritavancin and found out it was non-inferior to 7 to 10 days of Vancomycin for acute bacterial skin and skin structure infections. So get it straight, one single 1,200 milligram dose giving day one was non-inferior to 7 to 10 days of daily IV Vancomycin. In their clinical trial, they looked at 475 patients with Oritavancin, 479 patients with Vancomycin and the investigator says clinical curate at the end of the study 79.6 for Oritavancin versus 80% for Vancomycin. So again the single dose of Oritavancin was non-inferior to twice daily Vancomycin. Dalbavancin is another drug also just recently approved in May of this past year. That has the same sort of long half-life dosing. Now, this drug also acting in MRSA and VRE gave – you given a thousand milligrams so in 1 gram on day one followed by 500 milligrams one week later. In patients who have a creatinine clearance of less than 30, you give 750 milligrams the first week and then 375 milligrams the second week and there’s no dosage reduction for dialysis.
So they actually did a proof of concept study back in 2003. This drug has a very long history. It was originally came in front of the FDA, it was turned down by the FDA then another company picked it up, did some new clinical trials and now it’s recently been approved. But this was under the original time that it was being looked at. They did once weekly Dalbavancin versus what they called the standard of care. And they used three arms, the first arm was 1,100 milligrams of Dalbavancin, this is single infusion versus the thousand milligram on day one followed by 500 milligrams on day 7, followed by what they called standard of care. And standard of care could consist of any number of antibiotics or combination of antibiotics frequently used. So outcome by treatment group, what they found is at the end of treatment one dose had an 81% clinical success. That’s pretty good. But look at the follow up, that dropped one dose to 62%. So there was a major drop of only one dose was used. So the two doses of Dalbavancin, 94% at the end of treatment and then the follow up visit 94%. That’s why you see this drug now being given in their two dose regimen. 1 gram day one, 500 milligrams at day 7. Their phase III trial looked at Dalbavancin with that dosing we talked about versus Linezolid 600 milligrams for two weeks, 660 patients and what you can find here is a clinical curate the test of cure with Dalbavancin 88.9% with Linezolid 91.2%. So the drug is non-inferior to Linezolid given twice a day for 14 days. So this is the phase III on which they received their FDA approval. You can actually see it’s more recent in June of 14, once weekly Dalbavancin versus daily conventional therapy for skin infections. That was probably discover one and two trials and the numbers you can see here Dalbavancin for both trials 79.7 versus Vancomycin followed by Linezolid 79.8. So again similar numbers non-inferior to the IV followed by p.o. versus just the two doses of Dalbavancin. And this for example an interesting question. Where do we place these two drugs, the Oritavancin and the Dalbavancin these once weekly drugs? Well, certainly they’re expensive. The numbers I’ve heard and these are not confirmed but the Oritavancin, the one dose is a little bit more reasonable about $2,700, $2,800 for a dose. The Dalbavancin for the two doses between $4,500 and $5,000. Well I have guess what hospital pharmacies are going to want to carry these drugs? Hospitals tried to decrease the rate or decrease the money they spend on their formularies. These are just really expensive. Well hospitals be okay with losing the admission. I worked at a for-profit hospital. Their mantra is heads and beds. They liked to get the admission. And what happens if you take one of these patients, you give them one of these doses in the ED let’s say. They don’t need any more antibiotic. Well if you don’t need any more antibiotic, what’s going to happen to the hospital? Hospitals going to lose the admission because the patients not receiving hospital level care. So which patients would benefit? Certainly patients who have an infection severe enough for an IV but not hospitalization. That’s a relatively narrow range and maybe patients who are going to be non-adherent with either home IV therapy or even oral therapy. That might be a patient where these drugs are beneficial. But what setting is it going to be used? It’s going to be used in the ED, are the emergency docs going to feel comfortable giving a drug that’s going to be in a system for a full week? And keep in mind, that these are not dialyzable. So what happens if the patient has an adverse event? Now in fairness in the clinical trials, adverse events were extremely rare with these drugs but remember clinical trials are relatively limited numbers. If this goes in to broad, do these drugs going to broad usage, what happens if the patient has an adverse event and the drug can’t be removed from the system? So these are all questions that we have to look at when considering these new drugs. I’m fascinated by them from an antibiotic development/pharmacokinetic pharmacodynamics standpoint but I’m not really clear yet where the clinical utilization is going to be. So what’s in the pipeline? Certainly there are drugs like Pexaganan. Pexaganan is a topical antibiotic currently in a phase III trials for the treatment of mild diabetic foot infection.
It is effective against MRSA. Ceftabriol is an anti-MRSA cephalosporin. That was hoping to be approved about five years ago but got rejected. And just like Dalbavancin was picked up by another company who’s now developing it again. Then we have some anti-MRSA quinolones. Remoxicin. There’s a drug that just hit the news the other day and Forbes and hit the popular press because they found it has some soil called Teixobactin, I’m not even sure if I’m pronouncing that right. And then we have totally new categories of drugs effective against MRSA like FTSZ inhibitors. But the big question is are we going to need them? Currently, we have MRSA rates that are decreasing. Even if we have MRSA, we’re not so – that the outcomes are going to be any different than patients who don’t have MRSA. We now have nine FDA approved drugs for MRSA to treat either acute bacterial or complicated skin and skin structure infections. We also have all of those older drugs that aren’t FDA approved that we use for more mild infections. So we have a lot of drugs that are effective against MRSA in line of a disease that seems to be decreasing in numbers. But we don’t need all of these new drugs, I don’t know. That’s a big question that remains to be answered. But I will tell you what we do need is more research on diabetic foot infections for all of these new drugs to determine their placement in treating what we treat. Thank you very much.