Warren Joseph, DPM discusses the treatment of MRSA and other multi drug resistant organisms. Dr Joseph offers specific advice concerning which antibiotics to use in potentially life-threatening infections and examines pharmaceutical and evidence based data regarding how treatment decisions should be made.
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Warren Joseph, DPM
Roxborough Memorial Hospital
Editor - Journal of the APMA
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Male Speaker: Our last week for this portion before we got to break. So the only standing between you and the break is Dr. Joseph.
Dr. Joseph: I thought there was a panel discussion but go for the break. Thank you very much. I got my check already. I’m good. It’s really interesting that study about the radiologist because there was actually a very similar thing that was done looking at osteomyelitis by Andrew Meyr out of Temple where they gave some osteomyelitis specimens to four board-certified pathologist and in all sorts of [capital] [00:40] efficient and basically found no agreement on the pathologic diagnosis of osteomyelitis. So it’s really cool when some studies like that get done. Last lecture for me for today is talking about MRSA and some of the MRDOs, the multi-drug resistant organisms. I could give an entire lecture on infection control and multi-drug resistant organism with this one slide. This was a one-page article that was published a couple of years ago in the New England Journal of Medicine. Basically what they did is they took a healthcare worker and had him go in and do an abdominal exam with no gloves on a patient who was MRSA colonized. They then had him come out and stick their hand on an agar plate. You could see it on the left a perfect hand print of MRSA. They then had him go back and do another abdominal exam on the same patient, but this time using alcohol-based hand gel, then stick the hand down on the plate again. You could see no hand print. I mean this just goes to the importance of hand hygiene in infection control and in particular the spread of some of these organisms. That’s why when I go into the hospital, I carry my own can. I have some stuff. I don’t like the stuff the hospital uses. I use it before I see the patient, after I see the patient, after I write the chart or work on the computer. I use it three times. By the way. Nowadays in hospitals, you are being watched. Most hospital infection control and prevention on offices or specialist do actually randomly and kind of surreptitiously watch provider hand hygiene, because they have to track it according to the government. There have been some interesting papers on that recently. This is a patient who comes in with an open abscess. He had dropped a trashcan on his foot at work. I apologize for not changing the color on this. He came into our emergency department. So this was the culture. Now let’s just talk about how you diagnosed MRSA using a culture. So by looking at this culture, how can you tell that this was MRSA? Duh, it says MRSA. Not rocket science. But I want you to double check this. I want you to not just necessarily go with what the lab says. I actually want you to look for the – you’ll notice that methicillin does not occur anywhere on this line because methicillin is a drug of historical importance. Only it was the first of the semi synthetic gram staphylococcal penicillins had a lot of toxicity. It isn’t used anymore. So the drug they always run oxacillin. If you look at the oxacillin line, you’ll see it’s oxacillin resistant. In fact there was a move of foot in the infectious disease literature about 10 years ago to change the name of this from MRSA to ORSA, for oxacillin-resistant staph aureus. You see how far that got. So we’re still calling this MRSA. Now I have to ask you. Is this what we call CA, community-associated MRSA, also known as the USA 300 or 400 strain, or is this HA or healthcare-associated MRSA? Well, most hospitals are not doing genetic typing. So you have to do it phenotypically. You see all these sensitivities. How this organism is susceptible to trimethoprim sulfate and tetracyclines and a lot of other drugs. That means that this is a CA or a community-associated MRSA. CA MRSA is the only thing -- I can lecture for a whole hour just on CA versus HA MRSA. I don’t bother because it’s going away. Not MRSA but it’s decreased but that whole differentiation is going away as MRSA changes. But the CA MRSA contains something called a SCCmec4, staphylococcal chromosome cassette mec type 4 gene. I don’t except you to remember that. I’m just impressing you with my knowledge. But this gene is what’s called a short-segment cassette. So there’s not a lot of room on there for a lot of resistance factors. So it’s a fairly easy to treat organism. The problem is that this CA MRSA which is what we see all the time in the foot and on the skin structure infections is a more virulent organism when it comes to soft tissue infections. So the next question is what about clindamycin? Here you see it’s clindamycin susceptible. Can you use clinda? We touched on this a little bit with the previous lecture.
Well, you can’t depend on the clindamycin susceptibility. You have to go to the erythromycin susceptibility. If it’s erythromycin R, you can’t use clindamycin. Because if you use clindamycin, the organism contains what’s called an inducible enzyme which will turn the organism resistant to clindamycin on therapy. About 95%. Some labs call it a D test. I call this the poor man’s D test just looking at the erythromycin line. You can’t count on clindamycin for its antimicrobial activity because about 95% of MRSA is erythromycin resistant. But you can use clindamycin for the reasons we talked about before which is its toxin reduction. I like to say that it’s not your father’s MRSA. You know, MRSA has been around since 1961. Actually interestingly enough you know the first use of methicilin in the United States? 1960. It was less than a year from when methicillin was used until MRSA came around. There’s a truism in infectious disease as the bugs are always going to be smarter than we are. In this case, you could see what happened. But MRSA has been around since 196t1. Why are we only worrying about it since the mid 1990s? That’s because in the mid 1990s most are changed. You started getting these different genetic types of MRSA. Now there’s only like 10 different genetic types of MRSA. The CA and the HA MRSAs. But again, all we need to really worry about is the CA MRSA. I don’t know. When I get my infectious disease fellowship back in the mid 80s, I used to get excited when we have MRSA. We had an MNM conference about it. Now I say we get excited if we don’t have MRSA because it seems that a lot of people coming in do in fact have it. CA MRSA, it leads in skin-and-skin structure, blood stream pneumonias maybe not the case but at least in skin-and-skin structure does seem to be more virulent than the HA MRSA. So it’s a good news bad news. The good news is we have CA MRSA and it’s easy to treat. The bad news is it’s a more dangerous organism. But we always need to treat it, at least with antibiotics. How can I ask this? Of course we need to treat it, or maybe not. There have been a number of studies that have looked at this. [Indecipherable] [07:13] back in New England Journal back in 2005. Got people thinking about this. What they look at is they look at CA MRSA in three different communities and they found that there was no difference in treatment on whether the antibiotic was resistance or sensitive. The organism was resistant or sensitive to the antibiotic. No difference. How is this possible? Well it’s because how does CA MRSA present? It presents as an abscess. What is the pathognomonic phrase used by patients who come in when they have a MRSA infection? They say, “Doc, I have a spider bite,” right, or an insect bite. What’s the first question you asked them? Did you see the spider? Because unbearably they’ll say, “No. I just woke up with it.” Ladies and gentlemen, I’m 56 years old. I’ve never been bitten by a spider in my life, all right? Spider bites are not all that common. Of course me and my wife are planning and thinking about moving out here to Arizona and we heard that’s not true anymore. They’ve got spiders and scorpions and all sorts of other little creepy crawlies. Who the heck wants to shake out your shoe before you put it on every morning to make sure there are no scorpions crawling in there? We had to rethink this decision. But the point I’m trying to make is if a patient comes in to you and says, “Doc, I’ve got a spider bite,” that is a MRSA infection until proven otherwise. To the point that actually the CDC, if you go in the CDC.gov website, they actually have posters you can print off that say something to the fact as if you have an insect bite or if you think you have an insect bite, you probably don’t. It’s probably MRSA. That’s because it presents as an abscess. What’s the treatment of choice for an abscess? Incision and drainage. Yeah, my mentor in infectious disease is Jack [Lafraq] [08:56]. What he used to teach the best antibiotic known to man, drain them. Surgical incision and drainage. Incision and drainage without adjunctive antibiotic therapy was effective management of MRSA’s skin-and-skin structure abscess of less than five centimeters in immunocompetent children. This is in the pediatric literature but it’s been duplicated in the adult literature. Five centimeters. That’s two and a half inches roughly. That’s pretty big on the foot. So basically they’re saying you don’t need antibiotics in these cases. Medico legally? Different story. But the evidence doesn’t support the need for antibiotics when you do I&D. This is kind of a cool study. They took patients with MRSA abscess. Almost 88% of the patients were CA MRSA. They gave them placebo versus Keflex. Placebo one. Not meaning that placebo is the better antibiotic but it just means it doesn’t matter. Antibiotics are probably unnecessary after surgical drainage. Now this study came out. This is Moran’s work. It was published in the New England Journal in 2006. They looked at MRSA in the emergency department.
They found 59% or 60% of all staff skin-and-skin structure infections were found to have MRSA. Yet greater than 70% of patients were treated with the antibiotics and effective against MRSA. So their conclusion was that therefore every patient who comes in the emergency department with a skin infection should be treated as they have MRSA. That’s why every patient in the world that comes in the emergency departments now gets trimethoprim sulfite and a gram of vanco hanging in the IV. But interestingly enough if you actually read in Moran’s paper, not just the abstract, buried deep in the paper is this sense. There was no difference in outcomes between patients who were given MRSA active versus MRSA inactive antibiotics. They did a follow up to this study. Just published it about two years ago. They now find that over 90% of patients receive antibiotics that are effective against MRSA. That’s all that [dactrum] [10:26] is being given out there or that vancomycin that’s being given out there. When in fact it may not have been necessary. So basically for methicillin susceptible staff, we talked about that before. We have all these different antibiotics to use for MRSA. Scalpel blade is the antibiotic of choice. So let’s say a patient comes in with MRSA. We know scalpel blade is the drug of choice but let’s be realistic. We have to give him antibiotic. What are your choices? The mild infection, I would say I like the later generation tetracycline, in particular doxycycline. Hundred milligrams, q12 hours. Could you use minocycline? Absolutely. Why I don’t use that one? I don’t know. Just doxy comes first in the alphabet. I don’t know. I just got used to it. Flip a coin. Minocycline, doxycycline. There’s actually far better data on the use of minocycline or doxycycline for the treatment of these mild MRSA infections than there is for this universally used trimethoprim sulfite. I mentioned before there’s a reason we stopped using this drug 40 years ago. Let’s look at the adverse events associated with trimethoprim sulfite. Allergies, probably more common than penicillin allergies. Stevens-Johnson syndrome. I lectured about two years ago in Huntsville, Alabama to a group of family medicine physicians. Doc comes after me after the talk. He said interestingly you said about Bactrim. I’ve been in family medicine a long time. In my entire career I’ve seen one case of Stevens-Johnsons syndrome. In the last year I’ve seen six. That’s because everybody is getting this drug. Drug-drug interactions with other sulfite drugs like sulfonylureas in your diabetic population. Neurological problems, psychiatric problems. Paper published in Clinical Infectious Diseases about four years ago from the CDC. Look at ED admissions for antibiotic associated adverse events. Number one drug, trimethoprim sulfite. So I’m not a big fan of this drug. I tend to use the doxycycline or the minocycline. I should have put it in here with or without rifampin. For skin-and-skin structure, I tend not to use rifampin. For osteomyelitis, the literature is very, very good nowadays on for oral therapy of the MRSA osteomyelitis using a combination of let’s say doxycycline and rifampin. Either 300 milligrams q12 hours or 600 milligrams q24 hours. Clindamycin we talked about, meds to meds. Moderate to severe MRSA infections. We got linezolid, vancomycin, daptomycin, tigecycline I told you I’m not a big fan of, and the new one ceftaroline. There are actually six antibiotics, FDA approved for the treatment of complicated skin-and-skin structure infections caused by MRSA. The one I don’t put up here is televancin because it’s not really being marketed right now in the United States even though it is approved here. Vancomycin has been around a long time, since about 1958. I love the history of antibiotics. The name was actually derived from the word to vanquish. I don’t know. It’s kind of neat. But the original formulations were called Mississippi mud because they had so many impurities in it. It was like a brownish-colored powder. It since has changed and they’ve done – Lilly was the innovator and they have since done some very nice clear pure work. But there have always been some problems with vancomycin. It doesn’t work particularly well. It doesn’t have particularly good tissue penetration. Of course we’ve got toxicities and particular ototoxicities. Now we have an issue called MIC creep. Basically all of that means is the MICs for staph aureus are rising. It used to be said that you used to get an MIC for the MRSA and it would be .5, then it went up to .1. The patient I had last week, the MIC, the vancomycin was two. The problem is with MIC above one, you are treatment failures. For years, in all my writings, in all my lecture, and I’ve always said never ever look at an MIC. That holds. I never want anyone in this room to look an MIC. It gives you no good information unless you know all the PKPD, pharmacokinetic, pharmacodynamics of the drug. You don’t.
Don’t worry about it. Look at the S and the R. The only time I want you to consider looking at the MIC is if you’re considering vancomycin for MRSA. Then I want you to look at that MIC because if it’s anything above one, you may end up with problems. So then the issue comes up. How do you dose vancomycin? Well we always taught standard dosing. One gram q12 hours. You know in the IDSA, MRSA guidelines that are available same place, idsociety.org, to find those, where you can find the diabetic foot guidelines. It actually says for skin-and-skin structure infections, one gram q12 is okay. The problem is the pharmacists have kind of commandeered us. The pharmacists are now doing something called weight-based dosing, in the dosing of 15 to 20 milligrams per kilogram. Think of that. Think of that for me. You would be hanging bath tubs of vancomycin. The problem with this is that it may be dangerous. What throttle do you keep? We always used to be called you keep the throttle less than 10. Well the pharmacist, the farm diesel tell you nowadays, that you should keep your throttle of 15 to 20. I don’t. I keep throttle to 10 to 15. Why don’t I keep 15 to 20? Well the recommendations that the pharmacists are giving you are based on what’s called pharmacokinetic pharmacodynamics parameters. They do what are called Monte Carlo simulations. I love that name. Isn’t that exotic sounding? Monte Carlo simulation. They have found that the only way to get what’s called an AUCMIC ratio of vancomycin above 400 is to do dosing, thus this high weight-based dosing and keep throttle to 15 to 20. There’s only one small problem with that. There is no evidence to support that that works in practice. It might be okay with bloodstream infections or pneumonias, but certainly not skin-and-skin structure. But there’s very good evidence to show that keeping throttle to 15 to 20 blows out patient’s kidneys. Why is this an issue? Medico legally. I reviewed a malpractice case of a podiatrist who admitted a patient, wrote the one gram q12 of vancomycin. Then wrote as many of you probably do, pharmacy to dose. The pharmacist actually – I call them radicalized pharmacists. The pharmacists actually had a rubber stamp with the reference from the Society for Health System Pharmacist Guidelines to talk about weight-based dosing. It was a big guy, like my size. They put this patient on two grams q12 of vancomycin. Within seven days, the patient was in acute kidney injury on dialysis. They sued the podiatrist. They did not sue the pharmacist or the hospital. Do not give up your responsibility for dosing antibiotics properly. Pharmacist, I have a great relationship with our clinical pharmacist. Pharmacists are great people with whom to work. They have a vast amount of knowledge and they’re a great resource. But don’t take everything at the word. Read, learn what’s going on, learn the science. Everybody has been speaking, has been really pushing that. Here you see MIC creep has become an issue. As the MIC goes up, treatment failures go up. This study was actually in bloodstream infections. This is paraphrasing Bob [Mowring] [18:27] in the world of infectious diseases. Bod is considered Mr. Grandpas of infection. Brilliant, brilliant man up in Boston. If you have a vancomycin MIC of greater than one, you cannot achieve a level of vancomyin that is high enough to be both safe and effective. You should use alternative agents. This is a cool study that was done. Generic versus innovator vancomycin. What they did is they did three generic vancomycin products, tested against the original Lilly product, the originator. All generics passed FDA criteria. So they all met all the criteria the FDA needed for generic drug. Yet in clinical trials or at least in the in-vivo, the animal studies, every single generic vanco failed. Every single generic vanco failed. So what’s your pharmacy using? I guarantee you, they’re not using the innovator. Lilly doesn’t make it anymore. They sold it to another company. The point is yeah I know, but you know what, I’ve been on time with every lecture and all we have is a 30-minute panel after this. I’m just kidding you. Ceftaroline I mentioned before. It’s the first anti MRSA cephalosporin. It’s IV only. It has no pseudomonas limited anerobic activity. It’s not indicated in diabetic foot. I don’t see a use for it, but I will tell you there’s some exciting work being done on the combination of ceftaroline with a new beta-lactamase inhibitor called Avibactam, which is an anti ESBL beta-lactamase inhibitor which looks really, really exciting.
But that’s long ways off. Linezolid, you know about. Just finished up talking about the multi-drug resisting gram negatives. That’s three levels of multi-drug resisting gram negative. Number one is the ESBL, the extended-spectrum beta-lactamase. What that means in English is we have e-coli protease. These organisms that we use to look at cross eye and they’d run away, they’re now resistant to multiple antibiotics. They’re resistant to all penicillin, all cephalosporin and all beta-lactamase inhibitor compounds. But they’re still susceptible with most carbapenems and tigecycline. Then the next step up is what we call the [carbocadinase] [20:40] producing gram negative rods. They contain something called the CTXM enzyme. Also known as the Kleb. pneumo carbapenemase. Well it’s no longer a Kleb. pneumo anymore. It is spread through a lot of other gram-negative rods. This organism as the name implies is not as common as ESPLs but is resistant to carbapenems. There have been major outbreaks. Good Morning America. That’s where I get my science. Last year, reported a patient, an outbreak in Southern California, 350 patients in a hospital. Mortality rates with KTC, bloodstream infections, over 50%. Know what antibiotic they’re using because nothing works against it? Polymyxin B. Colistin. Talk about everything old is new again. We don’t even know how to dose these antibiotics. They blow our kidneys left and right. But with 50% mortality, you need to do it. Then the nasty. The metallo-beta-lactamase containing organisms called the New Delhi metallo-beta-lactamase. Where was the New Delhi metallo-beta-lactamase first found? No, actually Scandinavia. The patient was from New Delhi. This has actually been found in the ground water in New Delhi. That’s how prevalent it is. Every patient who has been found with this has either been an Indian national or has traveled to India for medical tourism. Really nasty stuff. Interestingly enough, the Indian government has called the US government to try to get the name changed because it’s kind of killing tourism there. Vancomycin failure rates are dramatically increasing in randomized control trials. Current pharmacy dosing guidelines for vancomycin should be reassessed. I think they are way too aggressive for a skin-and-skin structure infections and dangerous frankly. Why do we consider to use an obsolete 50 year old antibiotic? Here your ID people, your pharmacist is saying they’re saving the new drugs. Saving for what? Newer MDROs are supplanting MRSA as the organism to fear. These are the bugs that scare me. MRSA we can treat. When we’ve got these multi-drug resistant organisms with no antibiotics, that is the future and that scares the hell out of me. I’ll just end with one little comment here. There was an article, an editorial written in Journal of Antimicrobial Chemotherapy about three months ago which was really cool. It was called “Are we entering a second pre-antibiotic era?” Think about it. Thank you very much.