Diabetic foot osteomyelitis continues to be one of the more challenging entities to diagnose and treat accurately. Although there are established clinical practice guidelines set forth by the Infectious Diseases Society of America (IDSA), deviations from these guidelines often exist from one treatment facility to the next.1
Many physicians continue to dogmatically use the so-called “standard” regimen of six weeks of parenteral antibiotics for every patient with bone infection regardless of the clinical situation. Several recent studies have cast doubt on the superiority of parenteral agents versus oral agents, and have re-examined the need for surgical debridement.2-5
Accordingly, let us take a closer look at these issues and others in the diagnosis and management of diabetic foot osteomyelitis.
Can We Treat Diabetic Foot Osteomyelitis Without Surgical Intervention?
The question of whether osteomyelitis of the diabetic foot can be treated without surgical intervention is often debated. Many clinicians feel that osteomyelitis cannot be treated effectively if one does not excise infected bone early on in the infectious process. Other physicians have argued that one can address osteomyelitis with minimal debridement and appropriate antibiotic treatment, and that physicians should reserve surgical debridement for those patients who are unresponsive to treatment or those with limb-threatening infections.2
In their retrospective study of 147 patients with osteomyelitis, Game and Jeffcoate treated 113 patients with antibiotics alone. Of those 113 patients, 93 (82.3 percent) achieved remission without surgery. The remaining 34 either underwent minor amputation (28 patients) or major amputation (six patients). Of the 28 undergoing minor amputations, 22 achieved remission (78.6 percent).2
In both groups, the two most common oral antibiotic regimens were either amoxicillin/clavulanic acid (Augmentin, GlaxoSmithKline) or clindamycin in combination with ofloxacin or ciprofloxacin (Cipro, Bayer). If the researchers identified methicillin-resistant Staphylococcus aureus, they either added the following drugs to the regimen or substituted them for other antibiotics: trimethoprim (Bactrim, Roche), doxycycline (Vibramycin, Pfizer), fusidic acid (not available in the U.S.) or rifampicin (Rifadin, Sanofi Aventis).2
These findings form a strong argument against the 2004 study of 224 patients by Henke and colleagues, who maintained that “conservative management worsens lower extremity salvage.”6
What One Study Reveals About Using Oral Antibiotics Alone
A 2006 retrospective study by Embil and colleagues looked at the efficiency of oral antibiotics alone in the treatment of osteomyelitis of the diabetic foot.3 Operative facilities and home intravenous antibiotic therapy programs are not always available in more remote or rural settings. In these settings, oral antibiotics are often the only treatment options.
Typically, the treatment of osteomyelitis consists of debridement of infected tissue and bone along with a four- to six-week regimen of parenteral antibiotics. Some recent studies have described the use of a shorter course of parenteral antibiotics followed by a longer course of oral antibiotics.7-10 Embil and co-authors proposed that oral antibiotics with or without limited debridement is an effective way to treat osteomyelitis of the foot.3
The study authors diagnosed osteomyelitis if there was a grade 3 Wagner ulcer with drainage plus at least one of the following criteria: evidence of bone destruction on plain radiographs; localized increased uptake on technetium bone scan with or without gallium; bone at the base of the ulcer that one could see, probe or palpate; or a positive bone culture showing microbial pathogens.3
Culture results were available for 102 of 117 episodes of osteomyelitis. Of these cultures, the researchers obtained 74 from a deep swab of exudate overlying bone, five from bone, and 23 from both exudate and bone. In the 23 episodes in which both culture types were available, 17 (81 percent) identified the same organisms in both samples. Of the 102 cultures, 80 came back positive with aerobic gram positive cocci being the most common isolates (60 percent). This was followed by aerobic gram negative bacillus (33 percent) and anaerobes (7 percent). Overall, Staphylococcus aureus was the most common organism isolated as it showed up on 36 of the 80 cultures that came back positive.3
Of the 117 episodes of osteomyelitis in the study, 93 were treated with oral antibiotics with amoxicillin/clavulanic acid being the most commonly used single drug. Of the 93 treated in this manner, 81 (87 percent) were found to be in remission or improving at 50 weeks after the initiation of treatment. Of the 93 episodes, only 29 (31 percent) received an initial short course of intravenous antibiotic treatment for associated acute skin and soft tissue infections. In short, of the 93 episodes treated with oral agents, 75 (80.5 percent) went into remission (78 percent) without bone debridement after a mean duration of oral therapy of 40 weeks.3
Based on the findings of this study, it appears that oral antibiotic treatment may be a viable option when surgical facilities and intravenous antibiotic therapy are not readily available.5
Why Bone Biopsy Cultures Are Preferred
A 2008 retrospective study by Senneville and colleagues looked to identify criteria predictive of remission in non-surgical treatment of osteomyelitis of the diabetic foot.4
One of the variables they assessed was the efficiency of antibiotic treatment based on cultures obtained from bone biopsies in comparison to those cultures obtained from soft tissue swabs. Even though bone biopsy has been declared the gold standard for determining appropriate antibiotic therapy, only one of the recent major studies by Senneville and colleagues evaluated the effectiveness of non-surgical treatment of osteomyelitis of the diabetic foot using bone cultures to determine the appropriate antibiotics.4,11,12
Senneville and colleagues evaluated 50 patients at nine different treatment centers who were treated with conservative therapies. Of the nine centers, only four routinely used bone biopsies while the other five routinely used soft tissue swabs. Researchers obtained soft tissue swabs by running a sterile compress over the ulcer after a brief cleansing with sterile saline. They obtained bone biopsies in the operating room under fluoroscopic guidance, using an 11 gauge needle they inserted through a 5 to 10 mm skin incision at least 20 mm from the periphery of the ulcer.4
Antibiotic treatment was based on culture reports and the route of administration was either orally for the entire duration of treatment or a short course of intravenous antibiotics followed by a longer course of oral antibiotics. Other treatments included general wound care such as the use of alginates, hydrocolloids or hydrogels along with offloading of the affected area. They did not use topical antimicrobials.4
The researchers defined remission as the absence of any sign of infection at the initial site or any contiguous site they evaluated at least one year after the end of antibiotic treatment. Out of the 50 patients with forefoot osteomyelitis, remission without surgical debridement occurred in 32 (64 percent) patients with a mean duration of therapy of 11.5 weeks. The most commonly used antibiotics were fluoroquinolones, clindamycin and rifampin.4
Of all the variables analyzed, only bone culture-based antibiotic therapy was proven to be a predictive factor of remission based on univariate and multivariate analysis. Remission rates with bone culture directed therapy was 56.3 percent versus 22.2 percent without bone cultures.4
What You Should Know About Biofilms And Small Colony Variants
Neut and colleagues discussed the importance of biofilms and small colony variants (SCVs) in clinical infections in a 2007 study.5 Infections related to the biomaterials used for joint replacements are the second-leading cause of implant failure.5 Once microorganisms adhere to these materials, they have adapted several powerful mechanisms of evading host defenses and most treatment options including antibiotics. Much of the success of these organisms can be attributed to the production of biofilms, a protective layer made of polysaccharides and protein, and another lesser known phenomenon known as small colony variants.
Bacteria inside biofilms can enter a dormant state and remain that way until a situation such as depressed immune function awakens them, allowing them to cause a clinical infection. While in a biofilm, bacteria are 10 to 1,000 times more resistant to antibiotic treatment.13,14 Researchers have attributed this resistance to an inability of the antibiotic to penetrate the biofilm along with a slower metabolic rate of organisms residing deep in the biofilm. Researchers have also suggested that the biofilm slows the penetration of certain antibiotics such as vancomycin so the organisms in the biofilm are exposed to gradually increasing doses of the antibiotic instead of one strong dose.15
Small colony variants are an alternate form of the bacteria produced by some microorganisms, which have a slower growth rate, higher antibiotic resistance and possibly a greater ability to persist intracellularly than their normal counterparts. With some species such as Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, researchers have theorized that when bacteria cannot grow exponentially due to either an unfavorable environment or antibiotic treatment, they switch phenotype to a persister (survival cell) that neither grows nor dies under the current conditions.16-19 Once conditions become more favorable, they can switch their phenotype back and continue biofilm growth.
Persister cells and SCVs share many characteristics.5 Researchers have suggested that the low nutrient and oxygen levels deep in the biofilm cause the phenotype to switch these variants. Small colony variants grow much slower and form colonies that are 10 times smaller when grown on standard media.20 These colonies also produce little pigment, are non-hemolytic, show less coagulase production, and demonstrate greater resistance to aminoglycosides and cell wall antibiotics.
Since the growth and metabolism of these SCVs are so slow, they are easy to miss on routine laboratory cultures which are only grown for 48 hours. Researchers have demonstrated that SCVs in Staphylococcus aureus take six times longer to grow and it is advised that one should incubate cultures for at least six days.20,21
Small colony variants also produce less virulence factors. This subsequently limits cytokine production and leads to corresponding rises in C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR). Accordingly, these tests are unreliable in diagnosing a postoperative infection caused by SCVs. Fewer virulence factors lead to less cytokine production, which leads to no corresponding rise in CRP and ESR.
While SCVs are more resistant to certain antibiotics, when they are appropriately identified, they are still very susceptible to antibiotics that are effective against slow growing bacteria. These antibiotics include tetracycline, erythromycin and especially rifampin when one uses this in combination with a quinolone.
It remains to be seen what constitutes a gold standard of treatment of osteomyelitis. At present, there is no one antibiotic that has been proven to be far and away better than another. Evidence-based studies do not support the use of parenteral only therapy but rather give credence to the use of oral only therapy with highly bioavailable agents directed against biopsy recovered pathogens. The idea that small colony variants of S. aureus could evade host defenses, culture and antibiotics by remaining dormant in bone cells is an intriguing area of study, which will no doubt evolve over the years to come.
The diagnosis and management of lower extremity bone infections in diabetic and non-diabetic patients is on the verge of a breakthrough period, which should eventually result in better treatment outcomes for our patients.
Mr. Hoffman is a fourth-year student at the New York College of Podiatric Medicine.
Dr. Khan is an Assistant Professor in the Department of Medical Sciences at the New York College of Podiatric Medicine.
Dr. Kosinski is a Professor in the Department of Medical Sciences at the New York College of Podiatric Medicine.
Dr. Steinberg is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. Dr. Steinberg is a Fellow of the American College of Foot and Ankle Surgeons.
For further reading, see “What The Literature Reveals About Diabetic Foot Osteomyelitis” in the March 2009 issue of Podiatry Today.
To access the archives or get reprint information, visit www.podiatrytoday.com .
1. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004;39(7):885-910.
2. Game FL, Jeffcoate WJ. Primarily non-surgical management of osteomyelitis of the foot in diabetes. Diabetologia 2008;51(6):962-7.
3. Embil JM, Rose G, Trepman E, et al. Oral antimicrobial therapy for diabetic foot osteomyelitis. Foot Ankle Int 2006; 27(10):771-9.
4. Senneville E, Lombart A, Beltrand E, et al. Outcome of diabetic foot osteomyelitis treated nonsurgically: a retrospective cohort study. Diabetes Care 2008;31(4):637-42.
5. Neut D, van der Mei HC, Bulstra SK, et al. The role of small-colony variants in failure to diagnose and treat biofilm infections in orthopedics. Acta Orthop 2007;78(3):299-308.
6. Henke PK, Blackburn SA, Wainess RW, et al. Osteomyelitis of the foot and toe in adults is a surgical disease: conservative management worsens lower extremity salvage. Ann Surg 2005;241(6):885-92.
7. Bamberger DM, Daus GP, Gerding, DN. Osteomyelitis of diabetic patients, long term results, prognostic factors, and the role of antimicrobial and surgical therapy. Am J Med 1987; 83(4):653-660.
8. Haas DW, McAndrew MP. Bacterial osteomyelitis in adult: evolving considerations in diagnosis and treatment. Am J Med 1996; 101(5):550-561.
9. Lew DP, Waldvogel FA. Osteomyelitis. New Engl J Med. 1997; 336(14):999-1007.
10. Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect Dis 1997; 25(6):1318-1326.
11. Jeffcoate WJ, Lipsky BA. Controversies in diagnosing and managing osteomyelitis of the foot in diabetes. Clin Infect Dis. Aug 1 2004;39 Suppl 2:S115-122.
12. Senneville E, Yazdanpanah Y, Cazaubiel M, et al. Rifampin-ofloxacin oral regimen for the treatment of mild to moderate diabetic foot osteomyelitis. J Antimicrob Chemother 2001; 48(6):927-30
13. Mah TF, Pitts B, Pellock B, Walker GC, Stewart PS, O’Toole GA. A genetic basis for Pseudomonas aeruginosa biofilm antibiotic resistance. Nature 2003; 426(6964):306-10.
14. Widmer AF. New developments in diagnosis and treatment of infection in orthopedic implants. Clin Infect Dis 2001; 33: S94-106.
15. Jefferson KK, Goldmann DA, Pier GB. Use of confocal microscopy to analyze the rate of vancomycin penetration through Staphylococcus aureus biofilms. Antimicrob Agents Chemother 2005; 49(6):2467-73.
16. Cochran WL, Suh SJ, McFeters GA, Stewart PS. Role of RpoS and AlgT in Pseudomonas aeruginosa biofilm resistance to hydrogen peroxide and monochloramine. J Appl Microbiol 2000; 88(3):546-53.
17. Cogan NG. Effects of persister formation on bacterial response to dosing. J Theor Biol 2006; 238(3):694-703.
18. Lewis K. Persister cells and the riddle of biofilm survival. Biochemistry (Mosc) 2005; 70(2):267-74.
19. Stewart PS. Mechanisms of antibiotic resistance in bacterial biofilms. Int J Med Microbiol 2002; 292(2):107-13.
20. Bergoge-Berezin E. Resistance and new antibiotic strategies. The problem with staphylococcus. Presse Med 2000; 29(37): 2018-21.
21. Proctor RA, Van Langevelde P, Kristjansson M, Maslow JN, Arbeit RD. Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus. Clin Infect Dis 1995; 20(1):95-102.
22. Looney WJ. Small-colony variants of Staphylococcus aureus. Br J Biomed Sci 2000; 57(4):317-22.