Just over a week ago my good friend and colleague in lower extremity ID, Mark Kosinski, DPM, FIDSA and I were interviewed by Miriam Tucker, a reporter for Medscape, about a recent paper that compared 6 weeks vs 12 weeks of antibiotic therapy for DFO that did not undergo surgical debridement. The impetus for this interview was a study published in Diabetes Care by Tone, et.al. Here are links to the PubMed abstract for that paper, and the original interview on Medscape along with a link to David Armstrong’s excellent “diabeticfootonline” blog where, with his permission and my thanks to him, I am cutting and pasting his reporting of this below. Although the article is a bit longer than my usual posting, I think it is worth reading as both Mark and I discuss what is unique and interesting about this excellent study.
Dr. Armstrong’s Report:
UPDATED November 27, 2014 // Six weeks of antibiotics may be sufficient for treating patients with diabetic foot osteomyelitis even in the absence of surgery, a new randomized prospective trial finds.
The results from 40 patients seen at five French general hospitals between 2007 and 2009 were published onlineNovember 20 in Diabetes Care by infectious disease specialist Dr Alina Tone (Gustave Dron Hospital, Tourcoing, France) and colleagues.
Current guidelines by the Infectious Diseases Society of America (IDSA) call for 3 months or more of antibiotic therapy when diabetic foot osteomyelitis is not treated surgically or when residual dead bone remains after surgery. But in the new study, remission was achieved in about two-thirds of patients following either protocol (6 or 12 weeks of treatment).
The main finding of the study shows that “one can treat patients with diabetic foot osteomyelitis with only 6 weeks of treatment, despite infected bone [not being] removed,” principal investigator Dr Eric Senneville (Gustave Dron Hospital) told Medscape Medical News.
The primary aim of reducing the duration of antibiotic therapy “is to limit the pressure on bacteria and therefore to decrease the emergence of bacterial résistance,” he added, although he noted that the design of the current study did not allow this issue to be examined.
Also important and demonstrated in the trial, Dr Senneville said, was to reduce the number of adverse events related to antibiotics and risk of drug–drug interactions “because these patients usually have a lot of medications due to the frequent comorbidities reported in this population.”
Accumulating Evidence Addresses Several Important Issues
This is a “good, well-done, high level of evidence study. It’s what we need in these patients,” said Dr Warren S Joseph, consultant in lower-extremity infectious diseases (Roxborough Memorial Hospital, Philadelphia, Pennsylvania) and coauthor of the IDSA guidelines along with Dr Senneville, when asked for comment.
Dr Joseph pointed out that the results address several areas of debate in the field. Not only did the study authors find 6 weeks of treatment to be as good as 12 weeks, but antibiotics were primarily given orally rather than intravenously, and in half of patients they were not given empirically but started once culture results were obtained, with no difference in outcomes.
And, the study also reinforces the overall idea—still under debate—that nonsurgical treatment is acceptable for selected patients with osteomyelitis.
“The evidence is getting stronger and stronger that there are alternative methods for treating osteomyelitis—some without surgery, some without intravenous antibiotics, for varying lengths of time—that work every bit as well as that old standby of 6 weeks of intravenous therapy,” Dr Joseph told Medscape Medical News.
“That’s why this study is important. It’s adding to the accumulated evidence out there that we have newer ways to treat osteomyelitis than just about everybody in the world thinks is the right way to do it.”
Dr Mark Kosinski (New York College of Podiatric Medicine, NY) agrees: “This is a well-designed, multicenter, prospective randomized study that significantly adds to our knowledge about treating diabetic foot osteomyelitis.”
“It is heartening to see that this study utilized oral meds as its primary treatment regimen,” Dr Kosinski told Medscape Medical News. “Over the years, IV antibiotics have remained for many (for better or worse) the perceived gold standard for treatment of diabetic foot osteomyelitis. Despite emerging evidence to the contrary, many clinicians still doggedly cling to the notion that IV is superior to oral for treating chronic bone infection.”
But “adherence to such dogma leads to overutilization of parenteral meds (which should be best reserved for treating acute infection), increases healthcare costs (increases length of hospital stay, placement of peripherally inserted central catheter lines, infusion nurses, materials associated with IV meds, etc), and presents the possibility of infection of the IV line itself,” he added.
Reducing Antimicrobial Use
In the French study, participants all had osteomyelitis complicating a neuropathic foot without peripheral arterial disease. Empirical antibiotics were prescribed while waiting for culture results only if the treating physician considered it necessary.
Antibiotics were selected based on the culture results and patient comorbidities, and were given orally for the entire time or intravenously for 5 to 7 days followed by oral administration for the rest of the time.
Staphylococcus aureus was the most common organism cultured from bone samples, followed by coagulase-negative staphylococci and gram-negative bacilli. Most of the infections (45%) were polymicrobial.
Oral coamoxiclav was prescribed empirically while waiting for culture results in 45% of patients, and in four of those 18 patients the pathogen turned out to be resistant to the antibiotic.
Empiric use of rifampin was discouraged, with good reason, Dr Senneville told Medscape Medical News. “Rifampin should never be used as an empirical therapy because of the risk of selection of rifampin-resistant bacteria.”
However, rifampin was the most frequently used antibiotic based on culture results (in 76%), followed by a fluoroquinolone (70%). A combination of the two was used in 47%.
Antibiotic-related adverse events occurred in 6 (30%) of the 20 patients randomized to 6-week treatment and 10 (50%) of the 20 patients in the 12-week group. Gastrointestinal symptoms related to rifampin were the most common adverse event (three vs nine episodes in the 6- and 12-week groups, respectively). Other adverse events did not differ between the groups.
Remission, defined as (1) the absence of local or systemic signs of infection, (2) stabilized or improved radiographic abnormalities on plain X-rays assessed at the end of treatment and 1 year, and (3) complete, sustained healing of the wound responsible for the underlying osteomyelitis, occurred in 26 patients (65%).
There was no significant difference in remission rates between the groups, with remission rates achieved in 12 patients (60%) in the 6-week group and 14 patients (70%) in the 12-week group.
The authors couldn’t identify any specific parameter that appeared to be associated with patient outcome, including methicillin-resistant S aureus; five of seven patients with methicillin-resistant S aureus still achieved remission.
The median delay of 14 days between bone biopsy and beginning of documented antibiotic therapy may appear surprising, they note, “but we think that diabetic foot osteomyelitis is not an indication for urgent antibiotic therapy, especially in patients with no signs of inflammation of the foot, which was the case in 22 (55%) of our patients.”
Indeed, there was no difference in outcome between patients treated with antibiotics immediately after bone biopsy compared with those given them after microbiological results were available (P = .84).
They conclude that a further larger-scale study is warranted to assess other beneficial effects of a reduction in duration of antimicrobial therapy for diabetic foot osteomyelitis, especially with respect to the emergence of bacterial resistance and antibiotic-related adverse effects.
Evolving Views Regarding Antibiotic Therapy
Dr Kosinski said he is impressed with the study methodology, particularly the inclusion of a bone-biopsy-recovered pathogen after a 2-week antibiotic-free period. “Bone biopsies are underutilized as a diagnostic modality, yet transcutaneous bone biopsies are easy to do, have a low complication rate, and yield valuable information as to the infecting organism toward which to direct antibiotic therapy.”
However, he noted a limitation of the work: the exclusion of patients with peripheral arterial disease. “It will be interesting to see if future studies will support similar conclusions in patients with compromised arterial supply, which so many of our patients with diabetes suffer from.”
Dr Joseph praised the investigators’ three-pronged definition of remission, noting it has been a matter of debate and is also an issue for the US Food and Drug Administration, which hasn’t approved a new antibiotic for diabetic osteomyelitis in over 20 years.
“FDA doesn’t have good guidance for industry on how to do an osteomyelitis study. No one has ever come up with a good definition on what constitutes a cure of osteomyelitis. [The authors] have done a decent job here—though not perfect—of trying to define it.”
Dr Joseph also pointed out that the guideline recommendations of 6 or 12 weeks of antibiotic therapy for various clinical scenarios does not have good supporting evidence. Moreover, recent studies suggest that in some cases in which surgery is performed, just 3 to 4 weeks therapy, or even no antibiotics, is sufficient.
“What excites me about this paper is it’s just one more piece of the puzzle…here they’re using 6 weeks, but it’s primarily oral [and there was no surgery]. Other studies have used less than 6 weeks when they’ve surgically removed bone. Frankly, [the authors] might have been able to go 4 weeks and get just as good a result as at 6 weeks. They just didn’t test that. That might be a next step.”
Dr Kosinski concurs: “I am also pleasantly surprised to see that the length of treatment may be significantly shorter than once thought,” and that the notion that diabetic foot osteomyelitis is always a surgical disease “is changing.”
“Likewise for the route of administration,” he added. “We now have at our disposal, antibiotics with high bioavailability after oral administration, antibiotics that may help change the widely held notion that parenteral is always better.”
“I have no doubt that by the time of the next incarnation of the IDSA guidelines, studies such as this one will play a role in their revision,” he concluded.
The study authors have reported no relevant financial relationships. Dr Joseph is a consultant to Dipexium Pharmaceuticals and consultant/speaker for Merck. Dr Kosinski had no disclosures.
Diabetes Care. Published online November 20, 2014. Abstract