Point-Counterpoint: Osteomyelitis: Can It Be Treated With Antibiotic Therapy Alone?

Yes.

This author argues many patients with osteomyelitis either refuse surgery or are poor surgical risks. In combination with advanced dressings and frequent debridement to address biofilm formation, antibiotics can be effective for osteomyelitis.

By James McGuire, DPM, PT, CPed, FAPWHc

The typical medical surgical Point-Counterpoint on osteomyelitis begins with the “medical” physician at a disadvantage. The patient already has osteomyelitis, diabetes, advanced kidney disease and compromised vascularity. The clinician discussing the “non-surgical” side must then come up with an antibiotic concoction that maximizes antimicrobial destruction while minimizing damage to the kidneys at the same time. This clinician also recognizes that the best one might expect from antibiotic therapy is a 60 to 90 percent chance that the infection will be suppressed and a 10 to 40 percent chance that the bacterial persister cells may go dormant only to rear their ugly head again anytime in the next 50 years.^1,2 Who would want to take this side?

It is my contention that this discussion is like the farmer trying to figure out how to prevent the second horse from getting out of the barn when the first horse is long gone. The real medical management of osteomyelitis begins long before the wound probes to bone and the X-rays show cortical changes suggestive of a contiguous spread of bacteria from the wound to the underlying cortex.

Studies suggest that patients who see a podiatrist have a 29 percent lower risk of amputation and that those amputations follow a foot ulcer 85 percent of the time.³ Rogers and colleagues have estimated that regular podiatric care can reduce the risk of ulceration by 48 to 73 percent and the risk of amputation by 50 to 69 percent.⁴ It is my contention that most of those amputations involved osteomyelitis and that regular podiatric care and rapid intervention in the event of an ulcer can not only reduce the incidence of infection but osteomyelitis as well.

The “medical” management of osteomyelitis is everything from the control of blood sugars and education regarding diet and exercise to the aggressive management of small, inconsequential “ulcerations” due to tight shoes or a day of activity. The well managed patient has had education on the risk of even small breaks in the skin and quickly returns to the podiatrist for dressings and offloading that facilitate substantial reduction in the wound (at least 50 percent) within the recommended four-week critical window or “golden hour of wound healing.”⁵

The development of an ulcer, the infection of that wound and the arrival of osteomyelitis are failures of medical management. Surgical management, regardless of the degree of success, is putting lipstick on a very ugly pig and given the survival rate of the average patient with a diabetes-related amputation, five years later, the pig is dead. Maybe the medical side of this argument is not so bad.

Treating Chronic Osteomyelitis As A Bone Biofilm
The best model to date for understanding chronic osteomyelitis is that it is actually a bone biofilm.⁶ Up to 80 percent of human infections are biofilm-related and 99 percent of the bacteria in nature exist in persistent biofilms.⁷ Acute wounds have relatively few instances of bacteria in the biofilm form but 90 percent of chronic wounds have bacteria in biofilms.⁸ Using quorum sensing, these bacteria alter their phenotypes and become more virulent and resistant to antibiotics. Standard culture techniques are inadequate to provide the clinician with a true picture of the intricacies of the wound biofilm, which often has multiple species of bacteria existing in multiple phenotypical forms.⁹

After two years of utilizing polymerase chain reaction (PCR) and DNA sequencing analysis instead of standard cultures in our clinic, I believe a very high percentage of biofilms on our patients, even if their major organisms are not resistant, carry resistant bacteria. These bacteria can easily transfer those characteristics to the dominant organisms, thereby increasing the organisms’ ability to resist attempts by clinicians to eradicate them with standard oral agents. Staphylococcus aureus and coagulase negative Staphylococci are the most common causative organisms isolated from osteomyelitis and are aggressive biofilm formers.¹⁰ Biofilm formation on cortical and cancellous bone allows the bacteria to evade the body’s normal immune defenses and resist antiseptic and antimicrobial agents.

To date, the only way to treat a resident bone biofilm successfully is to remove it physically, hence the success in the surgical approach to the disease.¹¹ The problem with surgery is that not only are there thousands of patients who refuse amputation or disfiguring surgery, but many of the patients who are prone to ulceration and infection that lead to osteomyelitis are very sick people who are poor surgical risks.

I recall very well an 85-year-old patient with navicular and talar head osteomyelitis who had severe cardiac disease and whose cardiologist informed me that if he went under anesthesia, he would die. To make matters worse, he was in end-stage renal disease and his urologist informed me that any prolonged exposure to antibiotics would push him into dialysis.

So what does the patient inform me? “If I have to have an amputation or go on dialysis, I am going to kill myself.” If this seems farfetched, I assure you it was real and it exemplifies the dilemma many physicians face every day when they have to discuss the choices available to patients with osteomyelitis.

Even medical management is not as simple as choosing the right antibiotic and administering it for the standard four to six weeks. We currently choose most antibiotics because of their ability to kill planktonic cells. However, these antibiotics are relatively ineffective against bacteria in biofilms unless we remove those biofilms or debridement disrupts them sufficiently to allow the antibiotics to take effect, hence the need for surgical intervention. Even with these interventions, the recurrence rate is high.

According to Spellberg and Lipsky, it has been pretty well established that oral therapies can be as effective as parenteral therapy, provided the agent has the desired bioavailability.¹ Oral therapies are easier for the patient, have less risk of catheter problems and are less expensive than long-term parenteral therapy. Preferred agents include fluoroquinolones or trimethoprim/sulfamethoxazole (Bactrim, Roche) when one administers the antibotic for eight to 16 weeks and usually at higher doses (ciprofloxacin 750 mg BID and trimethoprim-sulfamethoxazole at 7-10 mg/kg/d of trimethoprim).¹

Many biofilms with Staphylococcus bacteria have Pseudomonas as a confounding partner, a particularly nasty bug when it comes to developing resistance and transferring that to the Staph. Pseudomonas also often exists primarily because of the favorable environment created by the Staphylococcus and will disappear as one treats the Gram-positive infection. For this reason, Gram-positive infections may respond better to trimethoprim-sulfamethoxazole or clindamycin.

Alternative choices for resistant Staph are linezolid (Zyvox, Pfizer) or doxycycline (Vibramycin, Pfizer). However, linezolid carries a fairly high complication rate when one administers it for long periods of time and clindamycin has limited clinical data supporting its use in osteomyelitis, according to Spellberg and Lipsky.¹ They also recommend the addition of rifampin (Rifadin, Sanofi-Aventis) (600 mg qD), showing that it increases cure rates for the above antibiotic regimens. They also recommend the addition of oral metronidazole for Gram-negative osteomyelitis (7.5 mg/kg every six hours (approximately 500 mg for a 70-kg adult).

A Closer Look At Antibiotic Beads And Local Injection
Local administration of antibiotics in high doses can occur by the insertion of antibiotic-impregnated beads such as polymethylmethacrylate (PMMA), which one removes after several days to weeks, or absorbable materials such as calcium sulfate or more recently synthetic polymers such as polylactic acid, poly(lactide-co-glycolides) and polyhydroxyalkanoates.¹² Gentamicin, vancomycin, clindamycin or tobramycin (TobraDex, Novartis) are the usual choices provided the bacteria are susceptible to them. Using them in combination may increase both the susceptibility and penetration of the antibiotics.¹³

The insertion of beads is not to take the place of surgery but one can use them when there are large dead spaces to fill, there is high suspicion of residual infected bone, or when only partial resection of bone is necessary for structural purposes. The advantages of implanted beads is their relatively high antibiotic concentrations in the area adjacent to the beads with little risk of systemic toxicity that occurs with oral medications. Beads are also considerably less expensive than oral agents.

Disadvantages are persistent drainage from the site with increased local inflammation and the need for a second surgery to remove the beads if one uses PMMA.¹²

Relatively few clinicians have proposed local injection or infiltration of antibiotics, and there is scant evidence to support its use.^14,15 I have personally used this technique on only a few patients with relative success in small distal articulations, such as phalanges and metatarsal heads, readily accessible by injection.

The most proximal injection attempt I made was on the aforementioned 85-year-old patient. After exhausting all options and determining susceptibility by biopsy, I injected vancomycin directly into the navicular and talar head three times per week for four weeks. This resulted in healing of the ulceration and at least dormancy of the osteomyelitis. The bone went on to ossify and remain infection-free for the next three years up until the patient’s death. At least he was able to keep his foot and kidneys for his remaining years.

I cannot advocate this form of administration from the literature but when the patient was backed into a corner and facing two relatively devastating alternative options, this did seem like the lesser of the three evils.  

In Summary
The lesser of evils is the usual choice once the osteomyelitis has developed and why Attinger and Wolcott advocate frequent debridement (once or twice a week) to remove and break up wound biofilms, and topical high-dose compounded antibiotics or antiseptics for use on the wounds.⁸ This is also why we recommend early, aggressive administration with advanced contact dressings such as hydrophobics, antiseptic impregnated materials, or high volume fluid absorption dressings.

There should also be daily flushing with hypochlorous acid or biguanide solutions with or without anti-biofilm surfactants to prevent biofilm formation of the wound. We use these daily in toothpaste to prevent the development of oral biofilms and a similar regimen is helpful in the prevention of wound biofilms.

From the surface biofilm doth the osteomyelitis arise. This coupled with effective offloading and protection of the wound will heal the majority of our ulcers and drastically reduce the number of referrals to Dr. Meyr.

Dr. McGuire is the Director of the Leonard Abrams Center for Advanced Wound Healing and an Associate Professor in the Departments of Podiatric Medicine and Biomechanics at the Temple University School of Podiatric Medicine.

Dr. McGuire thanks Timothy Greene, a fourth-year medical student who provided the research.

References

1. Spellberg B, Lipsky B. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2012; 54(3):393-407.
2. Widmer A, Barraud GE, Zimmerrli W. Reactivation of Staphylococcus aureus osteomyelitis after 49 years. Schweiz Med Wochenschr. 1998; 118(1):23-26.
3. Carls GS, Gibson TB, Driver VR, et al. The economic value of specialized lower-extremity medical care by podiatric physicians in the treatment of diabetic foot ulcers. J Am Podiatr Med Assoc. 2011; 101(2):93-115.
4. Rogers LC, Lavery LA, Armstrong DG. The right to bear legs-an amendment to healthcare: how preventing amputations can save billions for the U.S. health care system. J Am Podiatr Med Assoc. 2008; 98(2):166-168
5. Available at www.nihb.org/docs/01252012/6.%20Wound%20Management.ppt .
6. Walter G, Kemmerer M, Kappler C, Hoffman R. Treatment algoritms for chronic osteomyelitis. Dtsch Arztebl Int. 2012; 109(14):257-64.
7. Rhoads D, Wolcott R, Percival S. Biofilms in wounds: management strategies. J Wound Care. 2008; 17(11):502-8.
8. Attinger C, Wolcott R. Clinically addressing biofilm in chronic wounds. Adv Wound Care. 2012; 1(3):127-132.
9. Cowan T. Biofilms and their management: from concept to clinical reality. J Wound Care. 2011; 20(5):220-6.  
10. Mader JT, Mohan D, Calhoun J. A practical guide to the diagnosis and management of bone and joint infections. Drugs. 1997; 54(2):253–264.
11. Brady RA, Leid JG, Calhoun JH, et al. Osteomyelitis and the role of biofilms in chronic infection. FEMS Immunol Med Microbiol. 2008; 52(1):13–22.
12. Gogia J, Meehan J, Cesare P, Jamali A. Local antibiotic therapy in osteomyelitis. Semin Plast Surg. 2009; 23(2):100-106.
13. Penner M, Masri B, Duncan C. Elution charcteristics of vancomycin and tobramycin combined in acrylic bone cement. J Arthroplasty. 1996; 11(8):939-944.
14. Dillon R. Successful treatment of osteomyelitis and soft tissue infections in ischemic diabetic legs by local antibiotic injections and the end-diastolic pneumatic compression boot. Ann Surg. 1986; 204(6):643-9.
15. Meani E, Romano C. Treatment of osteomyelitis by local antibiotics using a portable electronic micropump. Rev Chir Orthop Reparatrice Mot. 1994; 80(4):285-90.

For further reading, see the DPM Blogs “Do Patients Really Need Four To Six Weeks Of IV Antibiotics For Osteomyelitis?” at https://tinyurl.com/44uxhns or “Are We Overdoing It With Antibiotics When Treating Osteomyelitis In The Diabetic Foot?” at https://tinyurl.com/n3trtvo .

For an enhanced reading experience, check out Podiatry Today on your iPad or Android tablet.

No.

Acknowledging ambiguities in the definition of osteomyelitis, this author argues that appropriate surgical resection can help patients attain wound-free ambulation.

By Andrew J. Meyr, DPM, FACFAS

It would be relatively easy for me to “drop the mic” (as our students would say) and walk away from this Point-Counterpoint argument because I work with Dr. McGuire and we often see the same patients. I could very simply ask him to explain that if antibiotics are able to treat osteomyelitis effectively, then why does he send patients who are on antibiotics from his outpatient wound care center to my inpatient surgical service with raging infections requiring partial foot amputations every Friday afternoon?

Of course, I partially jest and appreciate that it is not that simple, but I am a surgeon by trade and do generally recommend surgical resection for diabetic foot osteomyelitis as opposed to primary treatment with antibiotics alone. Although I accept that there are certainly some situations in which treatment with antibiotics as opposed to surgery is at least reasonable and that there is some limited evidence to support this practice, my personal most important clinical outcome measure when dealing with the diabetic foot is wound-free ambulation.^1-7

In other words, I want my patients to spend as much of their lives as possible with an intact soft tissue envelope, ambulating in supportive shoe gear and independently completing their activities of daily living. By the same measure, I want my patients to spend the least amount of time possible dealing with daily local wound care because of an open ulceration, having frequent physician visits, home nursing appointments, cumbersome offloading devices and limited/protected weightbearing. I want them to spend less time just having to expend mental and physical energy on their foot each and every morning when they wake up. That is without even mentioning the direct and indirect costs of long-term antibiotic therapy, of which I am most concerned with the potential for renal/hepatic insult and the development of resistant organisms.  

With an appropriately aggressive surgical resection, I can frequently generate an infection-free and intact soft tissue envelope with suture removal in two to three weeks. In other words, less than a month after presentation, I can typically have patients without bandages and antibiotics in supportive shoe gear and returning to their normal daily protocols. If I am really on my game and appreciating the root cause of their specific diabetic foot pathology, I can implement prophylactic procedures intraoperatively to create a relatively biomechanically stable foot that is not at significantly increased risk for the development of future problems.  

What Exactly Is Osteomyelitis?
That is an overly simple argument, however, and doesn’t necessarily get into what I really “think” about the topic. If I am really being honest with myself and our readers, I would admit that the question of whether antibiotics can effectively treat or “cure” osteomyelitis is a difficult one to answer. It is a challenging topic to debate because in all honesty, I am not exactly sure what the term “osteomyelitis” means.

Here is a little thought exercise. Patient 1 (left photo) has a hallux with localized cellulitis in the setting of a wound with a relative overload of necrotic soft tissue. I think most people would attack this pathology with local debridement and antibiotics in an attempt to “cure” this hallux of its infection. Patient 2 (right photo) has full-thickness gangrene of the hallux in the setting of localized cellulitis. I think most people would also attack this pathology with a similar plan: local debridement and antibiotics, but the local debridement would consist of partial foot amputation. I am not sure anyone would expect antibiotics to “cure” the hallux.

While antibiotics can help treat localized infection in the setting of viable tissue, I am not aware of any prescription that can bring tissue with gangrene back to life. Dead is dead, whether there is infection present and whether it is the surrounding soft tissue envelope or the underlying bone.  

So what exactly is “osteomyelitis”? Is it the potentially infected but viable osseous tissue as in Patient 1 or the potentially infected but dead/necrotic osseous tissue as in Patient 2?  

Let us take the thought exercise a step further. How did I come up with the diagnosis of “infection” for Patient 1 in the first place? Any number of sources tell me that there is no single diagnostic test that I can order to determine whether there is infection present in the soft tissue (skin, fascia, muscle, tendon, etc.) surrounding the bone of the phalanx.^8-14 While physical examination findings (presence of necrotic tissue or purulence, edema, cellulitis, warmth, body temperature, etc.), laboratory tests (white blood cell count, erythrocyte sedimentation rate, C-reactive protein, would culture, etc.), and imaging studies (plain film X-rays, magnetic resonance imaging, computed tomography, etc.) may help provide me with important supporting information, infection is first and foremost a clinical diagnosis.

Why then should I expect there to be a single diagnostic test to tell me if the bone directly underlying this surrounding soft tissue envelope is infected? Wouldn’t it make sense for bone infection to be defined clinically as well? At least in my mind, this should be particularly true with diabetic foot wounds and infections as these are almost always the result of contiguous extension in which the bone becomes involved only after penetration of all other superficial layers.¹⁵

So again, what exactly is osteomyelitis? Does it exist along a spectrum of “mild,” “moderate” and “severe” like we accept for soft tissue infections without a single diagnostic test? Is it more of a black-and-white issue with a single gold standard test that tells us definitively either yes, the bone is infected or no, the bone is not infected? In other words, can bone infection also exist along a relative spectrum?

A third consideration potentially complicating the issue of the definition of “osteomyelitis” is the fact that we rarely clinically consider bone in terms of its anatomic components of the cortex and cancellous portions. I believe this is an important point when considering bone pathology and healing potential because the two parts have distinct vascular supplies. The periosteum primarily supplies the cortex of bone, which is more likely to be disrupted in a diabetic foot infection via the contiguous extension mechanism. Nutrient arteries primarily supply the cancellous portion of bone, which would be relatively protected from an externally invasive infectious process. Particularly with respect to the potential treatment of osteomyelitis with systemic antibiotics, how can we expect the antibiotics to reach the specific pathologic and infected portion of bone? Has infection disrupted the vascular and capillary network, or is it intact?  

Understanding The Shades Of Gray With Osteomyelitis
These questions and thoughts rest at the crux of my misunderstanding of the term “osteomyelitis,” as well as whether I think a specific intervention can be expected to “cure” it. I am not sure there is anyone who would consider a dead piece of bone without an intact vascular supply or surrounding viable soft tissue envelope, and with associated positive clinical, laboratory and imaging findings as a candidate for antibiotics with the hope of a successful outcome.

In the same way, however, there may be a situation in which an acute bacterial infection is present in a segment of viable bone with an intact vascular supply and surrounded by a viable soft tissue envelope. Although we may consider both cases “osteomyelitis,” there is a significant clinical difference in the pathologic picture and expected outcome.  

To go even further, I also think these semantic differences directly relate to the problems we have with the specific diagnosis of osteomyelitis, whether it be from histopathologic, microbiologic, radiographic or laboratory means. Looking at the scope of our current knowledge as a whole, my contention would be that we generally view the pathogenesis, diagnosis and treatment of osteomyelitis as a definitive black-and-white issue. However, issues of “viable versus necrotic” and “spectrum of infection” likely bring a lot of underappreciated gray into the topic. This can often cloud and complicate our clinical judgment.  

In Conclusion
I am going to go out on a limb and reject the concept of “osteomyelitis” as being too “black and white” when dealing with contiguous extension in the diabetic foot, and instead recognize it is likely that a spectrum of infection and osseous viability exists.

My group is currently working on developing a Contiguous Extension Bone Infection Spectrum (CEBIS) to aid in the diagnosis and treatment of diabetic foot osteomyelitis that will take into account clinical findings (angiosome-specific arterial inflow, quality of the soft tissue envelope, location of ulceration/osteomyelitis relative to pressure, presence of neuropathy, specific exposure of cortical/cancellous bone, etc.), radiographic findings (specific plain film and MRI findings with respect to cortical integrity and cancellous involvement), laboratory findings (WBC, inflammatory factors, etc.) and patient factors (past medical history, ambulatory status, etc.).

I do not know if we will completely solve the issue but we are hopeful that we can objectively look at some of the “gray” that is certain to exist with this challenging pathology. 

Dr. Meyr is an Associate Professor within the Department of Surgery at Temple University School of Podiatric Medicine in Philadelphia.

References

1. Venkatesan P, Lawn S, Macfarlane RM, Fletcher EM, Finch RG, Jeffcoate WJ. Diabet Med. 1997; 14(6):487-90.
2. Senneville E, Lombart A, Beltrand E, Valette M, Legout L, Cazaubiel M, Yazdanpanah Y, Fontaine P. Outcome of diabetic foot osteomyelitis treated nonsurgically: a retrospective cohort study. Diabetes Care. 2008; 31(4):637-42.
3. Game FL, Jeffcoate WJ. Primarily non-surgical management of osteomyelitis of the foot in diabetes. Diabetologia. 2008; 51(6):962-7.
4. Game FL. Osteomyelitis in the diabetic foot: diagnosis and management. Med Clin North Am. 2013; 97(5):947-56.
5. Lazaro-Martinez JL, Aragon-Sanchez J, Garcia-Morales E. Antibiotics versus conservative surgery for treating diabetic foot osteomyelitis: a randomized comparative trial. Diabetes Care. 2014; 37(3):789-95.
6. Aragon-Sanchez J, Lazaro-Martinez JL, Alvaro-Afonso FJ, Molines-Barroso R. Conservative surgery of diabetic forefoot osteomyelitis: how can I operate on this patient without amputation. Int J Low Extrem Wounds. 2014; epub Sep 25.
7. Bonham P. A critical review of the literature: part II: antibiotic treatment of osteomyelitis in patients with diabetes and foot ulcers. J Wound Ostomy Ciontinence Nurs. 2001; 28(3):141-9.
8. Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, LeFrock JL, Lew DP, Mader JT, Norden C, Tan JS. Infectious Disease Society of America. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004; 39(7):885-910.
9. Dinh T, Snyder G, Veves A. Current techniques to detect foot infection in the diabetic patient. Int J Low Extrem Wounds. 2010; 9(1):24-30.
10. Brem H, Sheehan P, Rosenberg HJ, Schneider JS, Boulton AJ. Evidence-based protocol for diabetic foot ulcers. Plast Reconstr Surg. 2006; 117(7 Suppl):193S-209S.
11. Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Dravitz SR, Landsman AS, Lavery LA, Moor JC, Schuberth JM, Wukich DK, Andersen C, Vanore JV; American College of Foot and Ankle Surgeons. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg. 2006; 45(5 Suppl):S1-66.
12. Basile P, Rosenblum BI. Surgical management and stepwise approach to diabetic foot infections. In: Zgonis T (ed.) Surgical Reconstruction of the Diabetic Foot and Ankle. Lippincott, Williams & Wilkins, Philadelphia, p. 90-99.
13. Joseph WS. Bone and joint infections. In: Handbook of Lower Extremity Infections, Second edition. Churchill Livingstone, Philadelphia, 2003, pp. 54-79.
14. Dinh MT, Abad CL, Safdar N. Diagnostic accuracy of the physical examination and imaging tests for osteomyelitis underlying diabetic foot ulcers: meta-analysis. Clin Infect Dis. 2008; 47(4):519-27.
15. Lew DP, Woldvogel FA. Osteomyelitis. N Engl J Med. 1997; 336(14):999-1007.

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