New evidence-based guidelines on the management of diabetic foot infections reflect significant advances by researchers and clinicians, but the recent emergence of regulatory hurdles has slowed the development of new antibiotic drugs for treating those infections.
By Emily Delzell
The recently released Infectious Disease Society of America (IDSA) guidelines1 for treating diabetic foot infections (DFIs) build on almost a decade of important, robust research and offer perhaps the clearest evidence-based guidance to date for treating patients with these infections. Yet, at the same time, the challenge of antibiotic development for DFIs has become mired in bureaucratic issues.
“I think that the main thing for clinicians to be aware of [with regard to the 2012 guidelines] is that we now have a good understanding of the causes of diabetic foot infections and of approaches to managing the problem and, that if these infections are managed properly, then the high rate of amputation associated with them can be dramatically reduced,” said Benjamin A. Lipsky, MD, professor of medicine at the University of Washington in Seattle and lead author of the IDSA guidelines.
“This makes it incumbent upon people who see a patient with diabetes and a foot infection to feel comfortable managing the patient based on the available evidence, and, if they’re not, to consult with someone who is comfortable dealing with this kind of medical problem,” Lipsky said.
Although Lipsky said the numbers vary depending on the population studied, a 2012 review article found that 15% to 25% of persons with diabetes will develop a DFI in their lifetime and that 10% to 20% of these will require some level of amputation.2
New evidence supporting collaboration between practitioners is one of the most important aspects of the guidelines, said Warren Joseph, DPM, consultant for lower extremity infectious diseases at Roxborough Memorial Hospital in Philadelphia and coauthor of the 2012 recommendations, which were published in May in Clinical Infectious Diseases.
“We now have solid research on the importance of the multidisciplinary team approach, which at a minimum should involve someone working on the foot, someone working on the vascular supply, and someone with infectious disease expertise,” Joseph said. “A key 2009 paper spelled out the benefits of such teams and the competencies that people treating DFI need to have to save limbs.”
That paper, published in Eplasty, outlined seven skills associated with promoting the highest limb salvage outcomes in patients with diabetes and lower extremity ulcerations and infections.3 These are: assessing lower extremity circulation and potential for healing with noninvasive therapies; appropriately performing a neurologic workup to assess motor, sensory, and autonomic neuropathy; obtaining relevant culture data; performing wound assessment and staging/grading of infection and ischemia; performing site-specific bedside and intraoperative incision and debridement; initiating and modifying culture-specific and patient-appropriate antibiotic therapy; and performing appropriate postoperative monitoring to reduce reulceration and infection risk.
The IDSA guidelines note that a multidisciplinary diabetic foot care team with these skills can rapidly and appropriately treat DFIs with techniques that typically include debridement of dead tissue, appropriate antibiotic therapy and, if necessary, offloading pressure and improving blood flow to the wound area. Many patients with foot infections initially receive only antibiotic therapy, which is often inadequate unless accompanied by appropriate wound care and surgical interventions.1
Research4 conducted since the 2004 publication of the original IDSA DFI guidelines5 shows that many foot infections are treated improperly, including prescription of the wrong antibiotic and failure to address underlying conditions such as peripheral arterial disease (PAD).
The 2010 Observational Study of the Infected Diabetic Foot,4 for example, evaluated 291 patients hospitalized for DFI. Almost all had peripheral neuropathy, more than half had PAD, and almost 50% had osteomyelitis. In 56% of patients clinicians had to change the initial antibiotic because it proved ineffective against the cultured bacteria. In addition, PAD was associated with poor outcomes, but researchers noted it often went unaddressed by treating clinicians.
Lispky, who was also lead author of the 2004 IDSA guidelines,5 noted that, “Since 2004 there has been an enormous increase in the literature on diabetic infections, which allowed the 2012 panel to produce a much more comprehensive guideline. The new paper has 343 references, most published since 2004. I think what we have now is a more mature document in a new format of ten questions that we as a panel of experts thought were still the most germane as to how to manage these problems.”
These 10 questions (see Box) have extensive evidence-based answers. Lipsky and his colleagues labored to make the format and the language as clear as possible as he believes the widespread application of these recommendations can improve the substantial morbidity and mortality associated with DFIs.
“Readers will also notice that we use the word ‘I’ in the questions, as in, ‘In which diabetic patients with a foot wound should I suspect infection,’” he said. “That was done most deliberately as I want the clinician reading them to think, ‘It is my responsibility to take care of the patient. How should I do it?’”
Although these guidelines and the body of research they draw upon offer clarity as to the “how” of DFI management, Lipsky, Joseph, and others feel there are several significant barriers to the optimal implementation of the recommendations, including the lack of a Food and Drug Administration (FDA)-defined pathway for the conduct of research aimed at testing novel and existing antibiotics for treatment of DFIs. The 2012 guidelines also address obstacles surrounding development of antibiotics for DFI and other complicated infections, including osteomyelitis, and call specifically for the FDA and similar international regulatory agencies to clarify their requirements for the study of antimicrobial agents.
Blocked antibiotic development pipeline
This problem emerged in 2010 when the FDA changed its 1998 drug development guidance6 for industry from what it termed “complicated and uncomplicated skin and skin structure infections” to what it now calls “acute bacterial skin and skin structure infections [ABSSSI].” The 2010 ABSSSI guidance specifically excludes complicated infections, including DFI.
“This change means that we’re now stuck now without any way of knowing how to go forward with new antimicrobial products,” Lipsky said. “For example, I have been consulting with some companies that want to develop an antibiotic that is currently indicated for other conditions, but not specifically for diabetic foot, and they want to get an indication for diabetic foot infections so they can promote it for that—but they don’t know how. Similarly, there are companies developing new products that are not standard antibiotics but that can be used in a topical fashion for DFI and won’t drive resistance to the antibiotics we do need to use systemically.”
Regulatory officials are aware of the issue and FDA spokesperson Karen Mahoney told LER, “The FDA is actively working on a number of guidance documents regarding the development of antibacterial drugs for serious bacterial infections. We are not presently working on a separate guidance document regarding the development of antibacterial drugs for skin infections such as diabetic foot infections, which are excluded from the draft guidance.”
The reason behind the 2010 change goes back to the pre-antibiotic era and the lack of data showing that antibiotics are efficacious for treatment of DFI, said Joseph, who noted there are only three antibiotics currently approved for DFI (linezolid, ertapenem, and piperacillin/tazobactam).
“The FDA has not been able identify historical controls by which they can set their margins for clinical trials of DFI. They claim there is no evidence antibiotics make any difference in diabetic foot—they assume they do, they kind of empirically know they do, but there is not anything published that provides the data statisticians say they need to set noninferiority margins by which to design clinical trials,” he said. “What they are saying, essentially, is that without a placebo-controlled study that shows that patients with diabetic foot infections who don’t get antibiotics get worse and that patients who do get them get better they can’t set guidance for DFI studies.”
Infectious disease expert Brad Spellberg, MD, assistant professor of medicine at Harbor-UCLA Medical Center in Torrance, CA, also feels the lack of guidance is an issue in antibiotic development, though not the only one.
Spellberg is cochair of an IDSA task force that has put forth a proposal for a limited population antibacterial drug (LPAD) pathway that would allow for more rapid approval of urgently needed new antibiotics and would designate a lead federal agency to explore opportunities for public-private partnerships to spur antibiotic research and development. In March Spellberg gave a congressional briefing on LPAD, which he and others are hoping will be included in this year’s Prescription Drug User Fee Act reauthorization bill.
Despite Spellberg’s efforts to forge new branches along the regulatory path, he believes the number-one issue is finding funding sources for needed studies.
“In the diabetic foot I believe the greatest need is in research comparing an oral antibiotic strategy with an IV strategy—and I believe there are probably already existing oral therapies we should be using for this disease,” he said.
But this kind of research, said Spellberg, is not in the National Institutes of Health’s programmatic mission, which is focused on antimicrobial resistance. And the NIDDK [National Institute of Diabetes and Digestive and Kidney Disease], which recently showed what Spellberg called “sincere and substantial interest” in a trial of oral versus IV antibiotics in DFIs that he proposed, lacks the budget for the multimillion-dollar study.
That leaves the pharmaceutical industry, which does have funds but needs some reassurance that such studies will be conductible, the drug will have a reasonable chance of approval if endpoints are met, and that the market size is worth the investment, he said.
Yet, Spellberg said, “The only reason we need regulatory buy in per se is if you want to study an experimental agent. In that setting, let me just say that companies are vastly too deferential to the FDA. You do not need clinical trial guidance to take a protocol to the FDA and say, ‘I want to do this trial.’ The reason companies want guidance is they want to mitigate their risk. But I think if you develop a protocol with experts and take it to the regulatory agencies they will dialogue with you.”
Lipksy noted that companies could encounter problems with marketing that understandably make them reluctant to proceed without formal guidance.
“If you move ahead with [research for] a product you want to be able to know that you can advertise that product and tell people when they can use it,” Lipsky said. “You might be able to get those papers published, but you can’t advertise it that way.”
The FDA, he said, is struggling now to discover exactly what they should require of industry to prove that antibiotics work in DFIs.
“We’re talking to them about the need for placebo-controlled trials in mild infections, which is scary for us. We have also been looking back to the pre-antibiotic era for some guidance on what happened to people who had what was then called diabetic gangrene,” Lipsky said. “The FDA is going to try to work with biopharmaceutical companies that want to develop new treatments to come up with a new way forward.”
One potential strategy for conducting trials of antibiotics for DFI is to consider looking outside the US for support, said David Shlaes, MD, PhD, founder of Anti-Infectives Consulting in Stonington, CT, where he currently consults with pharmaceutical companies about antimicrobial development.
“They could perhaps negotiate a design in Europe—you could certainly start there and then go to the FDA with whatever it is you’ve negotiated,” Shlaes said. “The US market is declining compared with the rest of the world in pharmaceutical development in general and antibiotics in particular, so a company might be able to get approval, but the drug wouldn’t be available for promoting in American markets.”
However, except for highly resistant gram-negative organisms, sometimes involved in chronic ulcers, Shlaes doesn’t feel there is a serious lack of antibiotic options for DFI.
“Once a drug is approved for skin infection it will be used in the diabetic foot anyway,” he said.
Lipksy noted that osteomyelitis, which the panel also addressed in the 2012 IDSA guidelines, is another condition for which there is no FDA drug development guidance for industry.
“There are essentially no antibiotics that carry a specific approval for bone infections and no data that support the superiority of any specific antibiotic agent or route or duration of therapy,” he said.
Lipsky and colleagues in the UK are moving forward with a trial that may help others learn more about conducting studies in this area.
“In the blinded pilot study we’re comparing oral to intravenous antibiotic therapy for various kinds of complex musculoskeletal infections, including osteomyelitis,” he said. “We have quite a few participants enrolled and are hopeful that the oral regimens will work as well as the intravenous antibiotics because it’s much easier to treat people with oral antibiotics than to give them long-term intravenous antibiotics.”
1. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54(12):e132-e173.
2. Hobizal KB, Wukich DK. Diabetic foot infection: current concept review. Diabet Foot Ankle 2012 May 8. [Epub ahead of print]
3. Fitzgerald RH, Mills JL, Joseph W, Armstrong DG. The diabetic rapid response acute foot team: 7 essential skills for targeted limb salvage. Eplasty 2009;9:e15.
4. Richard JL, Lavigne JP, Got I, et al. Management of patients hospitalized for diabetic foot infection: results of the French OPIDIA study. Diabetes Metab 2010;37:208-215.
5. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004;39(7):885-910.
6. Guidance for Industry. Food and Drug Administration. Center for Drug Evaluation and Research. Uncomplicated and complicated skin and skin structure infections—developing antimicrobial drugs for treatment. 1998.
7. Guidance for Industry. Food and Drug Administration. Center for Drug Evaluation and Research. Acute bacterial skin and skin structure infections: developing drugs for treatment. 2010. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071185.pdf. Accessed May 31, 2012.