American College of Physicians: Internal Medicine — Doctors for Adults ®

Monday, November 24, 2014

Moxifloxacin for MRSA: Why is this not standard of care?

Moxifloxacin and MRSA. Why is this interesting?


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 Food and Drug Administration in 1999 for Avelox, the brand name they gave to moxifloxacin. A Japanese company had discovered in the 1970s 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 Streptococcus pneumoniaeand Staphylococcus 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 U.S. in 2014.


Methicillin-resistant Staphylococcus aureus (MRSA) 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. S. 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

The Journal of the American Medical Association featured an article entitled Clinical Management of S. 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 a pill. But that is compared to $8 a day plus administration 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.

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 S. 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 S. 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 S. 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.

Janice Boughton, MD, ACP Member, practiced in the Seattle area for four years and in rural Idaho for 17 years before deciding to take a few years off to see more places, learn more about medicine and increase her knowledge base and perspective by practicing hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling. Disturbed by various aspects of the practice of medicine that make no sense and concerned about the cost of providing health care to every American, she blogs at Why is American Health Care So Expensive?, where this post originally appeared.

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Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Iowa City, IA, with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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