Osteomyelitis: Causes, Symptoms, and Treatment

Osteomyelitis (majority osteomyelitis) is an infectious disease of the bone. It is often also referred to as chronic bone ulceration.

Osteomyelitis (bone ulceration) can be caused by specific infections, such as tuberculosis and many others. However, osteomyelitis is usually based on unspecific infections, which can be caused by bacterially by open fractures and operations. It is usually just as rare for pathogens to enter the bloodstream as it is for neighboring centers of infection to be spread. In addition to these bacterial osteomyelitides, osteomyelitis can also be caused by viruses and fungi in rare cases.

In the area of osteomyelitis caused by non-specific infections, a distinction is made between acute osteomyelitis and chronic osteomyelitis (chronic bone ulceration).

Acute osteomyelitis occurs in two different forms. A distinction is made between:

  • the endogenous – haematogenic form (= primarily located in the medullary cavity; a general disease with manifestation in the organ)
  • the exogenous form (= post-traumatic, postoperative; osteitis),

which can be discussed more explicitly below.

Chronic osteomyelitis also occurs in two different forms. A distinction is made here between:

  • the secondary chronic form
  • the primarily chronic form.

Acute osteomyelitis, regardless of whether the form is endogenous – haematogenic or exogenous, can become chronic if not treated appropriately (= secondary chronic form).

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Causes of osteomyelitis

In general, it can be said that almost all inflammatory diseases of the bone are due to infections with various pathogens. As a rule, these pathogens are bacteria.

The pathogen spectrum always depends on the type of infection. In most cases, Staphylococcus aureus is considered the pathogen spectrum. In addition, Pseudomonas aeroginosa, Klebsiella, Staphylococcus albus, streptococci, meningococci, pneumococci and Escherichia coli can also play a decisive role.

Streptococci as a pathogen spectrum are actually only relevant in hematogenic osteomyelitis in infancy and childhood.

As already mentioned, there are two pathways that can be held responsible for the development of acute osteomyelitis.

Either it is an endogenous – haematogenic osteomyelitis, in which case the pathogens are transmitted via the blood from a focus of infection outside the bone, or it is a so-called exogenous osteomyelitis, in which case infections are transmitted into the body via open wounds (accidents, operations).

Infections of an endogenous – hematogenous osteomyelitis can, for example, be sinusitis, tonsillitis, inflammation of the roots of the teeth, furuncles, etc.

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Osteomyelitis in childhood

Acute hematogenic osteomyelitis is a typical disease in children, especially between the ages of 3 and 15. Osteomyelitis in infancy or childhood usually occurs in the area of the long bones of the thigh (femoral metaphysis). The disease spreads under the periosteum (subperiosteum) and can spread into the bone marrow or via vascular connections into the adjacent joint. It leads to acute symptoms with fever, chills, severe local pain, swelling, redness, overheating and relieving postures.

As pathogens of osteomyelitis in childhood, so-called gram-positive pathogens (e.g. Staphylococcus aureus, Group A streptococci) are in the foreground. The targeted pathogen-sensitive antibiotic therapy of the disease also depends on this. In principle, haematogenic osteomyelitis should be considered in infants with pain in the extremities, redness, and swelling, and in poor general condition. If osteomyelitis is suspected in infants or children, the osteomyelitis disease must be diagnosed or ruled out by means of imaging (X-ray, ultrasound, magnetic resonance tomography) after a clinical examination.

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Diagnosis of osteomyelitis

In general, caution must be exercised with general infections, as hematogenic endogenous osteomyelitis occurs after general infections. A typical example of the development of endogenous haematogenic osteomyelitis in infancy is an infection of the umbilical cord.

If, for example, the above-mentioned symptoms occur during examinations of osteomyelitis, an acute inflammation of the bone can be assumed. The disease can also be detected in the blood. Typical for inflammations in the body is the increase in the concentration of white blood cells (= leukocytes; leukocytosis), as well as a significantly, increased blood sedimentation rate (= BSG). This diagnosis of osteomyelitis is only of importance in the case of an acute form since in the case of chronic osteomyelitis both values show only a moderate increase.

In the case of acute osteomyelitis, the pathogen can also be detected during the diagnostic procedure by means of a blood culture or puncture of the inflamed bone. This then also provides important information about the therapeutic measures to be taken in the course of an antibiotic treatment. Antibiosis must be specific to the pathogen in order to be effective.

Osteomyelitis usually only becomes visible in an advanced stage of the disease. Bone changes are usually only visible two to three weeks after the onset of the disease. Then, however, visible changes (cf. X-ray) in the form of calcifications (= ossifications), lighter spots and/or detachment of periosteum from the bone become apparent.

If osteomyelitis is chronic, blood vessel occlusion can lead to reduced blood flow to the bone, which may even lead to bone infarction. The result of a bone infarction is the death of certain bone parts, which then remain in the infected area as residual bodies (= sequesters). This can be recognized as a light-colored border in X-ray diagnostics since dead bone tissue is usually answered by the formation of new bone tissue. The light-colored border is therefore connective tissue.

Furthermore, the diagnosis of osteomyelitis can be made by sonography (= ultrasound examination). On the positive side, it should be mentioned that, for example, the detachment of periosteum from the bone, which is caused by the formation of abscesses, can be seen earlier than in the X-ray image.

A further diagnostic measure for osteomyelitis is the so-called skeletal scintigraphy. This diagnostic method enables the detection of inflammatory processes by means of very weak radioactive preparations (= radiopharmaceuticals).

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X-ray

Osteomyelitis can be made visible by imaging techniques. However, in acute osteomyelitis, the changes in the bone structure are only visible on X-ray after about one to two weeks. In the further course of the disease, the x-ray reveals spotty brightening, lifting of the periosteum from the bone and calcifications (ossifications). In chronic osteomyelitis, parts of the bone often die off, leaving behind a residual body (sequestrum), and new bone tissue forms around these bone parts. The resulting connective tissue around the residual body is visible in the X-ray image as a bright seam.

Therapy

If osteomyelitis is diagnosed at a very early stage, conservative therapy with targeted antibiotic therapy and immobilization is possible. A smear is taken from the spot of the focus and the pathogen causing the disease is determined. Then a specific antibiotic therapy is carried out until the inflammation parameters in the blood count normalize. In addition, adequate pain therapy (analgesia) must be ensured.

However, it is often necessary to carry out a rapid surgical intervention to clean up the focus. In this case the bone is drilled to relieve pressure (bone trepanation), thoroughly rinsed and the damaged bone areas removed. Antibiotic carriers are often inserted in order to achieve locally high levels of antibiotic action. Depending on the extent of the defect in the bone, bone transplants and several follow-up operations may have to be performed. Only through immediate therapy can the osteomyelitis heal without bone or joint damage. Often the therapy of osteomyelitis is a long process.

A distinction must be made between endogenous hematogenic osteomyelitis in infants, children and adults.

The therapeutic treatment of osteomyelitis in infancy is carried out by the administration of penicillins according to the pathogen spectrum and by immobilizing the affected body region with a splint or plaster cast. If a joint is affected by osteomyelitis, this joint is usually rinsed. This can work in different ways:

  • by puncture or
  • through a so-called flush-suction-drainage system.

If the osteomyelitis has progressed so far that the growth plate has already been damaged, secondary reconstructive measures may become necessary.

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The therapeutic treatment of osteomyelitis in children is carried out by targeted antibiotic administration in conjunction with immobilization by means of a splint or plaster cast of the corresponding body region. In very special cases, for example when residual bodies or abscesses are formed, surgical intervention may be necessary. Only in rare cases does a transition from the acute to the chronic form of osteomyelitis occur.

Therapy in adulthood is also carried out by means of targeted antibiotic administration in conjunction with immobilization using a splint or plaster cast. In contrast to infancy or childhood, the bacterial foci of osteomyelitis are cleared early in adulthood. In this process, parts of the bone that may have been removed must be replaced by so-called cancellous bone grafting (= transplantation of bone substance from another, healthy bone that belongs to the body) in order to maintain the functionality of the corresponding extremity. In addition, in the case of therapy, irrigation – suction – drains are inserted to flush foci out of the affected joints. In contrast to acute osteomyelitis in children, recurrence and transition to the chronic form of osteomyelitis often occurs in adults.

Complications

As already mentioned, in infancy and childhood there is a risk that the acute inflammation will cause damage to the growth zone (= metaphysis) of the affected bone. Under certain circumstances, this damage can cause severe deformities or shortening of the affected extremities.

There is a particular danger in the case of osteomyelitis up to the age of 2 years. At this age, the blood vessels of the medullary cavity run directly from the metaphysis (= growth zone of the bone) through the cartilaginous epiphysis joint into the pineal gland (= end piece of the bone; transition to the joint). As a result, the pathogens can also penetrate into the joints and cause purulent joint effusions there, which in turn can lead to severe joint damage and possibly even growth disorders.

Every acute endogenous hematogenous osteomyelitis, especially in adult patients, carries the risk of passing into the chronic form. This leads to considerable remodeling processes within the affected bone, under certain circumstances bone infarctions can occur, as a result of which certain parts of the bone are no longer supplied with blood and die. The dead bone parts then remain as residual bodies (= sequester) in the infected area. In addition, reactive connective tissue formation (= osteosclerosis) occurs, which reduces the elasticity of the bone and increases the risk of bone fractures. Adults in particular tend to form recurrent bone fractures.

Antibiotics

Decisive for the antibiotic treatment of osteomyelitis is the detection of the pathogen at the affected site. In any case, a blood test should be carried out, if necessary also a puncture of fluid accumulations and abscesses at the osteomyelitis focus in order to determine the pathogen. In the best case, treatment with antibiotics is pathogen-specific, immediate and is administered intravenously. In the acute inflammatory phase of osteomyelitis, it is crucial that the antibiotic is brought to the site of infection for a sufficiently long time. Furthermore, the concentration of the antibiotic at the site of action must be sufficient to kill the pathogen efficiently. As with any targeted antibiotic, it is important to test for resistance of the pathogen to various antibiotics in the best possible way. Treatment with the antibiotic clindamycin has proven to be advantageous because it effectively accumulates in the bone area and a complete cure of the disease can be achieved. Alternatively, an antibiotic treatment with penicillins (e.g. oxacillin, flucloxacillin) or cephalosporins can be used. As a rule, antibiotic therapy can be terminated when the rate of blood cell sedimentation (BSG, non-specific inflammation parameter) normalizes or when there are no symptoms.

Only targeted antibiotics prevent transitions to chronic osteomyelitis. In contrast, chronic osteomyelitis usually requires surgical intervention.

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Osteomyelitis of the calcaneus

As already described under Causes, endogenous – haematogenic osteomyelitis develops as a result of pathogens that are carried via the blood from a particular site of infection within the body into the bone marrow of a bone. They then settle there, which leads to the formation of abscesses. Abscesses are pus foci that the body can catch if the immune system is very good or good. Then they remain localized, while they often spread when the immune status is poor.

As can be seen from this, the course of the disease depends on individual factors, such as the immune defense, but also on the patient’s age.

In children up to the age of two years, blood vessels of the medullary cavity run directly from the metaphysis (= growth zone of the bone) through the cartilaginous epiphysis joint into the pineal gland (= end piece of the bone; transition to the joint).

As a result, the pathogens can also penetrate into the joints and cause purulent joint effusions there, which in turn can lead to severe joint damage and possibly even growth disorders.

With increasing age, the blood supply to the epiphysis joint decreases in childhood and adolescence until it is no longer supplied with blood at all later on. As a result, the infection of the bone marrow is then usually limited to the metaphysis, so that the joints are usually no longer affected.

The hip joint is the exception to the rule, however, since the metaphysis in the joint capsule is included there. Therefore, the joint can also be affected here.

However, as soon as the end of the growth phase is reached, the ossification of the cartilaginous components occurs. As a result, the protective border to the pineal gland joint is removed. As a result, in adults – similar to children up to two years of age – infections of the joints can reoccur.

In addition to the individually varying course of the disease, the virulence (= aggressiveness) of a pathogen also has an effect on the course of the disease. As a result, one and the same type of pathogen can, under certain circumstances, cause different severe types of the disease.

The spectrum then ranges from a mild disease with mild symptoms to acute, sometimes life-threatening symptoms or chronic course in chronic osteomyelitis.

There are forms of endogenous – haematogenic osteomyelitis, which often have a chronic course.

These are, for example, the so-called Brodie abscess, Paget’s disease or tuberculous osteomyelitis (see: definition).

Each of these diseases occurs very rarely compared to the other forms, but all of them have an individual clinical picture with very typical, individual disease patterns and courses.

Occurrence of osteomyelitis

According to scientific studies, endogenous osteomyelitis occurs predominantly in children and adolescents, with a specific incidence in the eighth year of life, usually after a general infection. Mostly the femur or tibia was affected by the disease. On average, boys seem to be more frequently affected by the disease than girls.

With regard to endogenous osteomyelitis in adulthood, it can be stated that this disease is rather rare. Similar to childhood and adolescence, men are affected more frequently than women. Endogenous hematogenic osteomyelitis in adulthood includes the long tubular bones (e.g. tibia) and the spine.

Symptoms

Endogenous hematogenous osteomyelitis generally proves to be a disease of the entire body in infancy and toddlers and usually manifests itself with a fever of up to about 40° C. In addition, depression and shivering become noticeable. Areas affected by the inflammation of the bones become noticeable by severe redness, swelling and pressure pains.

The symptoms mentioned above are usually less severe in adults. Other typical symptoms are depression, pain and functional limitations in the affected areas. The inflammation of the corresponding area can become noticeable by a slight overheating (possibly also redness), but these types of symptoms are much less pronounced in relation to infants and toddlers.

As already mentioned several times, such an illness can become chronic under certain circumstances. In this case, the pain in the affected areas, including functional limitations, is the main focus.

Prognosis:

In acute hematogenic infant osteomyelitis the chances of recovery are good with early therapy. In cases in which the disease has already progressed and has caused the destruction of the growth plate, sometimes considerable growth disturbances can occur.

Even in the case of acute haematogenic osteomyelitis in childhood, the prognosis depends considerably on the damage to the growth plate. Here too, considerable bone damage can occur, which can lead to shortened extremities under certain circumstances.

The same applies to acute endogenous haematogenic osteomyelitis in adults:

If the disease is diagnosed in time and treated consistently, healing is usually possible without permanent damage. There is, however, a risk that the disease – if not detected early and treated appropriately – will turn into chronic osteomyelitis.

In comparison to the acute form, chronic osteomyelitis is difficult to treat and tends to flare up even in the case of successful healing (renewed infection of the bone).

Exogenous osteomyelitis

Exogenous osteomyelitis is an inflammation of the bone marrow, which is either caused by an open wound after an accident (= post-traumatic) or during an operation (= postoperative). In both cases germs penetrate from the outside and spread in the wound area in such a way that a local inflammation initially develops within the bone. As in endogenous haematogenic osteomyelitis, the main pathogens include Staphylococcus aureus, but also Escherichia coli and Proteus. Other bacterial pathogens can also be considered as disease triggers.

The course of the disease is very individual and depends on various factors. The extent to which pathogens can spread into and from bones depends primarily on the individual immune defense of a patient. This means that especially patients with a reduced immune defense (for example after a transplantation, caused by a so-called immunosuppressive therapy) are affected by acute, but also chronic courses of osteomyelitis.

In addition, patients with a deficient blood supply to the bone are also at risk. This is the case, for example, with patients suffering from diabetes mellitus (= diabetes) or arteriosclerosis (= hardening of the arteries).

Frequency

Due to the history of development (post-traumatic, postoperative) of exogenous osteomyelitis, it is understandable that this disease occurs predominantly in adults.

Statistical surveys show that men tend to be more frequently affected by accidents than women so that it can be concluded that men are also more frequently affected by this disease than women.

Symptoms

In the acute form of exogenous postoperative osteomyelitis, the first symptoms can be seen as early as three to four days after surgery. The patient usually reacts with fever, swelling and redness of the affected area and possible wound secretion. Patients also often complain of pain and depression.

Comparable symptoms are seen in posttraumatic osteomyelitis.

In such cases, rapid intervention is required to prevent the transition to secondary chronic osteomyelitis.

Diagnosis

The occurrence of the above-mentioned symptoms in combination with a traumatic experience or as a result of an operation already allows the conclusion of the presence of exogenous osteomyelitis.

As a rule, a further diagnosis is made by means of a blood analysis. In this process, the CRP value is measured as an inflammation barometer, as is the blood sedimentation rate (BSG), which is significantly increased in the case of osteomyelitis. Typical for inflammations in the body is also the increase in the white blood cell concentration (= leukocytes; leukocytosis). However, these diagnostic measures are only of importance in the case of an acute form, since in the case of chronic osteomyelitis both values show only a moderate increase

The osteomyelitis usually only becomes visible on X-rays at a more advanced stage. Bone changes are usually only visible two to three weeks after the onset of the disease. Then, however, visible changes (cf. X-ray image) in the form of calcifications (= ossifications), lighter spots and / or detachment of periosteum from the bone become apparent.

If osteomyelitis is chronic, blood vessel occlusion can lead to reduced blood flow to the bone, which may even lead to bone infarction. The result of a bone infarction is the death of certain bone parts, which then remain in the infected area as residual bodies (= sequesters). This can be recognized as a light-colored border in X-ray diagnostics since dead bone tissue is usually answered by the formation of new bone tissue. The light-colored border is therefore connective tissue.

Furthermore, sonography (= ultrasound examination) can be used for diagnosis. On the positive side, it should be mentioned that, for example, the detachment of periosteum from the bone, which is caused by the formation of abscesses, can be seen earlier than in the X-ray image.

As a further diagnostic measure, the so-called skeletal scintigraphy can be used. This diagnostic method enables the detection of inflammatory processes by means of very weak radioactive preparations (= radiopharmaceuticals).

therapy:

Therapeutically, both conservative and surgical treatments can be applied. Due to frequently existing poor local blood circulation conditions, conservative antibiotic therapy has little chance of cure, since only an insufficient concentration of active substances can be achieved at the intended location.

For this reason, an exogenous osteomyelitis is usually treated surgically. This can be done in different ways, but we would like to mention a few examples here:

  • The surgical radical removal of the focus of inflammation, possibly combined with cancellous bone grafting (= transplantation of bone substance from another, autologous, healthy bone), irrigation and drainage.
  • The insertion of irrigation – suction – drainage.
  • The systemic antibiotic therapy over a period of one to about one and a half months.

Complications

Exogenous acute osteomyelitis can degenerate into a serious disease of the entire body and – in unrecognized cases – even lead to sepsis (= blood poisoning), which in turn can have serious consequences, such as organ damage.

Rapid intervention is required in the case of exogenous acute osteomyelitis, as the transition to secondary chronic osteomyelitis is fluid. Chronic osteomyelitis has far less chance of healing and can lead to pronounced bone remodeling processes up to bone stability disorders as a result of bone infarctions.

It is also possible that the disease can spread to neighboring joints, resulting in considerable restrictions of movement. In severe cases, stiffening and shortening of limbs (amputations) may even occur as a consequence.

Summary

If the disease osteomyelitis is detected early, there is a chance of healing without any remaining damage. As already mentioned, the therapy is usually carried out surgically, as conservative antibiotic therapy rarely works due to the poor blood supply to the bones. Since the transition to the secondary – chronic form of osteomyelitis is fluid, healing often proves difficult (see above). The chronic osteomyelitis tends to form recurrences even after possible healing successes so that the disease can flare up again and again.

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Resources

  1. Beck-Broichsitter BE, Smeets R, Heiland M. 2015. Current concepts in pathogenesis of acute and chronic osteomyelitis. Curr Opin Infect Dis 28:240–245. doi:10.1097. [PubMed] [CrossRef] [Google Scholar]
  2. Lew DP, Waldvogel FA. 2004. Osteomyelitis. Lancet 364:369–379. doi:10.1016/S0140-6736(04)16727-5. [PubMed] [CrossRef] [Google Scholar]
  3. Walter G, Kemmerer M, Kappler C, Hoffmann R. 2012. Treatment algorithms for chronic osteomyelitis. Dtsch Arztebl Int 109:257–264. doi:10.3238/arztebl.2012.0257. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  4. Schleifer KH, Kandler O. 1972. Peptidoglycan types of bacterial cell walls and their taxonomic implications. Bacteriol Rev 36:407–477. [PMC free article] [PubMed] [Google Scholar]
  5. Garrity GM, Boone DR, Castenholz RW. 2005. Bergey’s manual of systematic bacteriology, 2nd ed, vol 2 Springer, New York, NY. [Google Scholar]
  6. Kornacki J, Doyle MP. 2010. Principles of microbiological troubleshooting in the industrial food processing environment, 1st ed Springer, New York, NY. doi:10.1007/978-1-4419-5518-0. [CrossRef] [Google Scholar]
  7. tto M. 2010. Staphylococcus colonization of the skin and antimicrobial peptides. Expert Rev Dermatol 5:183–195. doi:10.1586/edm.10.6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  8. Madigan M, Martinko J, Stahl D, Clark D. 2012. Brock biology of microorganisms, 13th ed Benjamin Cummings, San Francisco, CA. [Google Scholar]
  9. Lowy FD. 1998. Staphylococcus aureus infections. N Engl J Med 339:520–532. doi:10.1056/NEJM199808203390806. [PubMed] [CrossRef] [Google Scholar]
  10. Tuchscherr LP, Buzzola FR, Alvarez LP, Caccuri RL, Lee JC, Sordelli DO. 2005. Capsule-negative Staphylococcus aureus induces chronic experimental mastitis in mice. Infect Immun 73:7932–7937. doi:10.1128/IAI.73.12.7932-7937.2005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  11. Foster TJ, Geoghegan JA, Ganesh VK, Hook M. 2014. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol 12:49–62. doi:10.1038/nrmicro3161. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  12. Dinges MM, Orwin PM, Schlievert PM. 2000. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev 13:16–34. doi:10.1128/CMR.13.1.16-34.2000. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  13. Otto M. 2012. Molecular basis of Staphylococcus epidermidis infections. Semin Immunopathol 34:201–214. doi:10.1007/s00281-011-0296-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  14. Calhoun JH, Manring MM, Shirtliff M. 2009. Osteomyelitis of the long bones. Semin Plast Surg 23:59–72. doi:10.1055/s-0029-1214158. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  15. Oryan A, Alidadi S, Moshiri A, Maffulli N. 2014. Bone regenerative medicine: classic options, novel strategies, and future directions. J Orthop Surg Res 9:18. doi:10.1186/1749-799X-9-18. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  16. Waldvogel FA, Medoff G, Swartz MN. 1970. Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med 282:198–322. doi:10.1056/NEJM197001222820406. [PubMed] [CrossRef] [Google Scholar]
  17. Pichichero ME, Friesen HA. 1982. Polymicrobial osteomyelitis: report of three cases and review of the literature. Rev Infect Dis 4:86–96. doi:10.1093/clinids/4.1.86. [PubMed] [CrossRef] [Google Scholar]
  18. Brady RA, Leid JG, Calhoun JH, Costerton JW, Shirtliff ME. 2008. Osteomyelitis and the role of biofilms in chronic infection. FEMS Immunol Med Microbiol 52:13–22. doi:10.1111/j.1574-695X.2007.00357.x. [PubMed] [CrossRef] [Google Scholar]
  19. Alguire PC. 2009. Internal medicine essentials for clerkship students 2. American College of Physicians, Philadelphia, PA. [Google Scholar]
  20. Lima AL, Oliveira PR, Carvalho VC, Cimerman S, Savio E. 2014. Recommendations for the treatment of osteomyelitis. Braz J Infect Dis 18:526–534. doi:10.1016/j.bjid.2013.12.005. [PubMed] [CrossRef] [Google Scholar]
  21. Pasquet J, Chevalier Y, Couval E, Bouvier D, Bolzinger MA. 2015. Zinc oxide as a new antimicrobial preservative of topical products: interactions with common formulation ingredients. Int J Pharm 479:88–95. doi:10.1016/j.ijpharm.2014.12.031. [PubMed] [CrossRef] [Google Scholar]
  22. Merritt K. 1988. Factors increasing the risk of infection in patients with open fractures. J Trauma 28:823–827. doi:10.1097/00005373-198806000-00018. [PubMed] [CrossRef] [Google Scholar]

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