Sunday, October 5, 2014
Moxifloxacin for MRSA (methicillin resistant Staph aureus): Why is this not standard of care?
The drug company Bayer applied for a patent on yet another drug in the flouroquinolone category of antibiotics in 1989 and received approval by the FDA (Food and Drug Administration) in 1999 for Avelox, the brand name they gave to moxifloxacin. A Japanese company had discovered in the 1970's that adding a flourine to relatively ineffective antibiotics in the quinolone family, such as nalidixic acid, made them dramatically more active, thus creating flouroquinolones. That discovery led to the development of norfloxacin, then ciprofloxacin and levofloxacin which have become mainstays of antibiotic therapy. Ciprofloxacin is extremely useful for treating urinary infections and a variety of other serious infections including anthrax and traveler's diarrhea. Levofloxacin has become one of our drugs of choice for treating pneumonia and is especially useful because it achieves the same levels when given by mouth as it does by intravenous injection. Moxifloxacin hasn't really caught on to the same extent, even though it also is absorbed extremely well when taken orally and achieves particularly high levels in the lungs. It is also more effective for treating infections caused by gram positive organisms than ciprofloxacin or levofloxacin, including resistant Strep pneumoniae and Staph aureus. It is approved for treating skin, lung and abdominal infections caused by susceptible organisms and in some hospitals (like the VA, I hear) it is the least expensive flouroquinolone option due to deals with the manufacturer, so it is used more often. It just became available in a generic form in the US this year (2014).
Methicillin resistant Staphylococcus aureus has grabbed headlines as it has become more common, both as a bug acquired in the hospital and now in the community, that is to say outside of hospitals. In some places resistant staph infections are now more common than the ones that are sensitive to the antibiotics we use most often. Staph aureus is usually quite a virulent bug, spreading aggressively in infected tissue and often seeding the bloodstream and even establishing itself on heart valves. It can cause particularly severe pneumonia, especially in already ill hospitalized patients and patients from nursing homes. It has become an especially big problem among intravenous drug abusers who are some of our sickest patients anyway, with coexisting issues like HIV infection and lack of adequate medical care. We have struggled to find antibiotics which work for MRSA and have turned to older and sometimes less effective antibiotics as well as newer and absurdly expensive ones.
A few weeks ago, while treating a patient with a MRSA infected wound, a colleague who is a wound care doctor suggested using moxifloxacin to treat her infection. I thought he was maybe just a little stupid, not to know that MRSA is usually resistant to flouroquinolones. I told him as much, except the stupid part and he told me that I was wrong, that he had just heard a talk at a wound care meeting and that moxifloxacin was good for MRSA. I checked the microbiology sensitivity sheet for my patient's MRSA to see what antibiotics it was sensitive to, and it was, indeed, resistant to levofloxacin and ciprofloxacin and our lab did not even test for moxifloxacin. I started poking around in the literature to find out what supported his claim that moxifloxacin was good for MRSA. There wasn't much, but there was an article that showed that, using MRSA from 12 patients who acquired it in the community or the hospital, moxifloxacin was more effective in killing the staph than trimethoprim sulfamethoxazole, linezolid or clindamycin. Another article showed that moxifloxacin was more effective than vancomycin, a standard treatment for MRSA, in treating MRSA in experimental biofilms, like the bacterial mats that characterize infected wounds. A third one looked at the effectiveness of vancomycin, ciprofloxacin and moxifloxacin at curing experimental heart infections (endocarditis) in rats and found that moxifloxacin was more effective than vancomycin and that ciprofloxacin didn't work at all. There were no human studies comparing moxifloxacin, head to head, with other standard antibiotics such as vancomycin for MRSA. So I guess he was right and I was wrong.
Standard of Care
This week's JAMA (Journal of the American Medical Association) featured an article entitled Clinical Management of Staphylococcus aureus Bacteremia, A Review, by Thomas L. Holland MD et al. The article concluded that vancomycin and daptomycin (a moderately toxic and very expensive new antibiotic for MRSA) are the first line antibiotic choices for MRSA bacteremia , that is infection found in the blood. This was based on 81 studies, none of which looked at moxifloxacin. The antibiotics studied were pretty much all the newer, recently released, very expensive and usually intravenous antibiotics. Studies involving humans are very expensive to perform, and funding is usually from pharmaceutical companies attempting to show that their drug works, which will make back the money they spend in research if all goes as planned. To give the article credit, the final conclusion was that well-designed studies to address the management of S. aureus bacteremia are needed.
Sepsis and Pneumonia
The standard of care in the hospitals where I have practiced is to use vancomycin (along with other broad spectrum antibiotic coverage) for patient who are seriously ill, in whom MRSA is suspected. Vancomycin is a difficult antibiotic to use, requiring measurement of levels to assure it is effective but not reaching toxic levels. It can cause kidney failure and hearing loss and if it is given quickly can cause "red man syndrome" which is what it sounds like, and quite disconcerting, though not deadly. Vancomycin must be given slowly which is a bit of an issue when a person is dying of rapidly progressive infection. But that's not actually the whole problem. We tend to use vancomycin when we suspect that there may be resistant staph in the lungs, but vancomycin actually has poor lung penetration and, even at standard doses, falls to what are probably ineffective levels during treatment.
It is often difficult to exclude pneumonia as a cause of serious infection in a patient who presents with sepsis, and the usual approach is to clobber them with broad spectrum antibiotics to cover whatever they might have. We try to get the antibiotics in to the patient as soon as humanly possible, ideally within an hour of arrival. Sometimes, however, it is difficult to get an intravenous line started and so a central venous catheter is placed, which must wait for a physician to do it, usually. Then there is a chest x-ray done to make sure that the line is in the right place and there is no lung collapse complicating the procedure. Then come the antibiotics. It can be agonizingly slow to get that first dose of life-saving antibiotics into a patient. Moxifloxacin can be given orally. "Here, take this." Bloop. Done. Or it can be given intravenously, if gut function is questionable, but quickly. Moxifloxacin covers most gram negative and gram positive organisms as well as atypical lung pathogens that cause serious infection including MRSA. Moxifloxacin dose is 400mg once daily and need not be adjusted for kidney or liver function.
So what is the catch?
What is wrong with moxifloxacin and why are we not using it more commonly? Moxifloxacin does not reach adequate levels in the urinary tract to treat urinary tract infections, which can be the cause of sepsis. But we can evaluate the urine quite quickly, in minutes actually, and adequately rule out urinary tract infection. Moxifloxacin can cause liver failure and serious skin rashes, but liver failure is extremely rare and all antibiotics cause skin reactions in some patients. It can cause tendons to rupture, similar to other fluoroquinolones, though that is also pretty rare. Moxifloxacin isn't cheap, somewhere between 5 and 20 dollars a pill. But that is compared to $8 a day plus high administration and monitoring costs for vancomycin and about $300 for daptomycin, plus administration costs. And moxifloxacin is now generic and produced by over 30 companies worldwide so its cost will likely become negligible. The biggest issue is that it hasn't been adequately studied in the setting of serious infection and isn't likely to be studied because it will make nobody money to do the expensive research. There is some evidence that staph aureus can become resistant to moxifloxacin in cultures, but, although this would certainly limit its usefulness, there has been no studies that I can find showing that this is actually relevant clinically, and some evidence implies that it might not be.
If, by some chance, it were to be studied and found to be superior to our present goofy standard of care, it would make some pretty profound changes in the way we do things. If moxifloxacin could be used to treat Staph aureus bacteremia then patients would not have to remain in the hospital or have outpatient intravenous antibiotics for 2 weeks, or 4-6 weeks in the case of complicated infections. It is incredibly inconvenient and dangerous to have patients on intravenous antibiotics for a prolonged amount of time. Intravenous drug abusers cannot be allowed to go home with an intravenous catheter in place because they will use it to inject drugs and the catheter will become infected. Those patients end up becoming fixtures in our hospital wards, often bored and disruptive, as they finish their prolonged treatments. When they leave against medical advice without completing their course of treatment a significant number will return, gravely ill, with a recurrence of their infection. The intravenous lines themselves, in addition to being very expensive, can cause infections and blood clots. Moxifloxacin achieves nearly identical levels when given orally as it does when given intravenously, so there would be no need for IV lines for 2-6 weeks.
In light of this information, what now?
I am not prepared to go against the standard of care at this point and use oral moxifloxacin for Staph aureus bacteremia, except in patients for whom intravenous therapy is impossible or likely to cause harm. I am, however, likely to use it for sepsis, when the urinary tract is not the source, in place of vancomycin plus other empiric gram negative and atypical organism coverage. I am also likely to choose it for treatment of wounds in which Staph aureus and gram negative organisms are identified or suspected. It is more than about time that adequate research was done to determine how we should use this drug for Staph, especially MRSA bacteremia.