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Chronic Osteomyelitis in Adults

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DOI: 10.1002/9781119720676.ch20

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Publisher : John Wiley and Sons, Inc
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Title (main) : Bone and Joint Infections
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Chapter 20

Chronic Osteomyelitis in Adults

Felix WA Waibel, Benedikt Jochum, Ilker Uçkay

Introduction
Chronic osteomyelitis (OM) in adults is an infection involving the bone marrow, the cortex, the periosteum,
and sometimes also the surrounding tissues [1]. The medical terms osteomyelitis and osteitis are
interchangeable, despite different meanings in detail. Usually, osteitis derives from an infection starting with
a cortical involvement, or including the bone solely. OM may usually derive from the bone marrow that can
subsequently infect the cortical bone [2], or underlines a simultaneous involvement of bone and marrow.
In case of fracture-related OM, an international expert group recently established the term “fracture-related
infection” instead of “osteomyelitis,” as the primary problem is the presence of a microbial biofilm on the
implants [2]. OM is mostly caused by bacteria and more rarely by fungi. However, rare immunologic disorders
such as SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis), idiopathic bone marrow
edema [3], or recurrent multifocal osteomyelitis closely imitate OM, but are not caused by microorganisms
(see Chapter 22) [4]. “Foreign bodies” or “devices” are also frequently associated with OM. Due to their clinical
significance, implant-associated chronic bone infections are discussed in separate chapters (see Chapters 23,
24). Similarly, diabetic foot and OM of the jaws are addressed separately (see Chapters 21, 22). Acute OM in
adults is presented in Chapter 18 and OM in children in Chapter 17.

Classifications of chronic OM according to its duration or origin are frequent (see Chapter 16). Of note, in
surgical practice, chronic OM equals the presence of sequestra, involucra, sinus tracts, and bone deformities
requiring surgical interventions. From a microbiologic point of view, most episodes of chronic OM are caused
by bacteria. Fungi are typically observed in intravenous drug users [5], in the immunocompromised host
[6], and to some extent in patients with diabetic foot OM. Parasites (i.e. echinococcosis) rarely cause OM
[7], while reports of viral bone infections are limited to case reports in the past [8]. Staphylococcus aureus,
Streptococcus spp., and Gram-negative germs such as Pseudomonas aeruginosa are the most common
pathogens [1]. Anaerobes are rare [9]. Kingella kingae typically causes arthritis and OM in children under the
age of 4 years [10] (see Chapter 8). Subacute OM due to tuberculosis and brucellosis is addressed in Chapter
19.

Pathogenesis
OM begins locally and develops in different steps. First, fibronectin receptors and/or several surface matrix-
binding proteins enable the adhesion of many pathogens (i.e. S. aureus) to bone matrix [11,12]. Following
adhesion, polysaccharides and proteins from the infecting bacteria and the host create a biofilm, which
represents a community of microorganisms generally resistant to host defense and most antimicrobial agents
(see further in Chapter 18). Additionally, planktonic pathogens can also change their metabolism and shape in
order to better fit in a silent and chronic phase of infection. For example, different microorganisms, especially
S. aureus, can form small colony variants (SCVs), which are “dormant,” i.e. metabolically less active than the
wildtype. SCVs typically have an increased phenotypic antibiotic resistance [13]. They are triggered by adverse
conditions such as antibiotic exposition at subinhibitory concentration, low pH environment (abscesses), or
nutrient deficiency. SCVs persist intracellularly, or inside the biofilms, until their environment improves,
when they revert to the wildtype and cause apparent infection [13]. Of note, biofilms play a crucial role both
in foreign body-associated infections, but also in implant-free OM [12,14]. The canalization of the osteo-
canalicular system of bone is another route of chronification that was described for S. aureus OM, and that
may be responsible for failure of infection eradication and late recurrences [15,16]. When local infection leads
to thrombosis of periostal vessels and ischemic necrosis occurs [11], parts of bone segments are separated from
vital bone within a short period of only eight days (sequestra) [17] and become substrate for bacterial adhesion
[1,11]. Within 48 hours of infection, the first abscesses usually appear [11]. Activation of osteoclasts leads to
osteopenia [1], while concomitant osteoblastic activation leads to formation of new bone (involucrum) (Figure
20.1). Bone destruction and new bone formation is a complex process mediated by osteoclast activation via
bacterial proteins and the resulting immune response [18]. For example, S. aureus protein A directly binds
to osteoblasts, inhibiting mineralization processes and proliferation. Furthermore, it activates osteoclasts via
binding to the TNF receptors expressed on the osteoblasts [18]. Plenty of evidence additionally underlines the
role of growth factors, drugs, cytokines, and hormones in regulating the osteoblastic and osteoclastic activity,
with specific mechanisms depending on the underlying pathogen [1,11].
 Figure 20.1. Involucrum with “new” bone formation inside an infected tibia. Image is displayed with the
permission of the patient.

Diagnosis

Clinical and Microbiological Diagnosis

Generally, the proof of infection in an altered or previously operated bone is complex and very often requires
not only clinical evaluation, but also laboratory, histological, and sometimes radiological workup (see Chapter
2). A common clinical appearance of chronic OM is local pain, accompanied by local or systemic inflammatory
signs such as swelling, warmth, localized fluctuation, functional impairment, and a sinus tract with occasional
purulent discharge (Figure 20.2). While a purulent sinus tract is a strong indicator for chronic OM, the
microbiological proof is assured by two or three microbiological samples from the bone [19] that show the same
microorganism(s). Superficial microbiological swabs on the bone surface are misleading, and should therefore
be avoided. As an exception, the probe-to-bone test is frequently used in diabetic foot OM (see Chapter 21).
However, it has little value for non-diabetic chronic foot OM. An “antibiotic window” of one to two weeks
is recommended before biopsy/surgery to avoid false-negative results. In addition, histologic analysis should
be performed in at least one bone biopsy. The presence of ≥5 granulocytes per high-power field confirms
infection and may allow differentiation between colonization and infection [20]. Pathogen-specific Polymerase
Chain Reaction (PCR) may contribute to the detection of difficult-to-grow pathogens, such as Bartonella spp.,
Brucella spp., Coxiella burnetii, Kingella kingae, Mycobacterium tuberculosis [21], or M. ulcerans [22] [19].
Of note, a specific PCR, upon the suspicion of a particular pathogen, can also be helpful in cases previously
treated with antibiotics (see Chapter 4). This may allow detection of the specific pathogen in cases with false-
negative culture due to the inhibitory effect of the systemic antibiotics [23]. PCRs provide a high specificity,
but a low sensitivity, and no susceptibility data with a few exceptions (e.g. methicillin- or rifampin-resistance).
 Figure 20.2. Painful swelling, reddening, skin atrophy, and orifice of a sinus tract over the distal tibia of
a patient with a 10-year old chronic osteomyelitis.

Imaging Procedures
Plain radiographs are always the first imaging modality for chronic OM, since they allow to rule out other
entities such as fractures or tumors [24]. Signs of OM are focal bone lysis or cortical loss, periostal reaction
or elevation, formation of new bone (Figure 20.1), regional osteopenia or trabecular pattern [25], soft-tissue
swelling, and – as radiological pathognomonic signs – presence of sequestrum, involucrum, or cloaca [24].
Computed tomography (CT) (Figure 20.3) is useful for surgical planning, and provides a higher velocity and a
higher patient comfort than magnetic resonance imaging (MRI). For bone, it combines a good sensitivity and
better prize-quality ratio than the MRI [26]. MRI has shown an excellent sensitivity (93%) and high specificity
(79%) for OM prior to surgical treatment [27]. In cases of posttraumatic OM, sensitivity, specificity, and
accuracy of MRI are reported as 100%, 69%, and 78%, respectively [28]. Several nuclear medicine techniques
are available for OM [29]. They are inferior to MRI in performance [30]. The role of scintigraphy is diminishing
given today’s more accurate methods [31].
 Figure 20.3. Bone lesions and sclerosis in a calcaneum (posttraumatic chronic osteomyelitis). Image is
displayed with the permission of the patient.

Treatment

General Considerations
Chronic OM should be managed in a multidisciplinary approach involving orthopedic surgeons, infectious
disease specialists, nurses, physiotherapists, and other medical specialties if necessary. The main question is
whether the patient needs a burdensome and invasive treatment. Many surgical interventions are complex
and difficult to perform and may impair everyday activities [19,32]. The decision must be based on various
aspects, such as patient’s general condition, comorbidity, as well as overall life expectancy. The substantially
cumbersome and often mutilating therapy should only be started if the patient is likely to profit in terms
of his/her quality of life. A chronic infection that chronically drains from a sinus tract is, per se, not an
indication for treatment. Likewise, a long-term suppressive antibiotic therapy should not be started in a stable,
asymptomatic patient. Instead, an intermittent suppressive therapy may be useful for a limited time during
symptomatic exacerbations of chronic OM (e.g. purulent discharge, pain). There are two major rules for a
curative approach in OM. First, a long-lasting cure is impossible, as long as the underlying reason for OM is
not eliminated. In these situations, infection is only the complication of a much more serious condition. Even
if the actual episode is cured, the underlying problem will very likely provoke a future new episode at the same
localization. Demonstrative examples of this non-resolved situations are sacral OM, e.g. in tetraplegic patients,
or diabetic foot OM in patients with Charcot arthropathy. Second, apart from few exceptions, chronic OM in
adult patients is still considered a surgical disease [1,33,34]. Evidence for the conservative eradication of OM
by antibiotic therapy alone still only exists in cases of hematogenous childhood OM, skull and maxillar OM,
vertebral OM, and diabetic toe OM in selected patients. Sequestra, biofilms, and necrosis may compromise
antibiotic effectiveness. Therefore, patients should accept one or multiple debridements and a hospital stay of
one (amputation) or several weeks (resection and reconstruction).
Surgical Approach
We summarize surgical options without detailed review of the techniques, which are reported elsewhere
[19,33,35]. Cornerstones of the surgical approach include sequestrectomy, resection of scarred tissue [1,34],
restoration of blood supply, dead space obliteration, bone stabilization, and adequate soft-tissue coverage
[34–36]. A profound theoretical knowledge alone is insufficient, even for otherwise experienced surgeons. All
these techniques require training in a specialized center and extended practical experience in OM surgery.
Intra-operative fistulographies using methylene blue can ease the excision of fistula [37]. Several bone biopsies
should be taken and analyzed both by microbiology and pathology. Prior antibiotic prophylaxis or treatment
should be avoided. Generally, clinical and visual resection margins larger than 5 mm probably are associated
with a better outcome in terms of cure, emphasizing an aggressive and meticulous debridement strategy [38].
In case of impossible blood flow restoration, or in the presence of grotesque bone deformations and large
effected bone areas, direct amputation can be considered [39].

Dead spaces should be filled, either with surrounding tissue, muscle flaps [33], or free tissue transfers
[40,41]. Tissue coverage is paramount to achieve cure and to prevent recurrence. A remaining dead space after
debridement is an important risk for recurrent soft-tissue infection and subsequent OM, because it creates an
avascular environment with a low pH, which is filled with blood. Both the low PH and the blood are conducive
to bacterial growth. Hence, ideally the optimal dead space obliteration should provide antibacterial properties,
structural stability in case of bone insufficiency, promote local bone growth, and lack of local or systemic
toxicity. Several strategies exist for obliterating dead space: biologic filling approaches with either local or free
muscle flaps; or bone auto- or allografts with or without local antibiotics [41]. Reaching comparable efficacy in
resolving OM, fascio-cutaneous and perforator free flaps may offer a higher patient satisfaction and aesthetic
result compared to muscle flaps [42]. In 2011, Tan et al. [43] published 35 OM cases treated by vacuum-
assisted negative-pressure closure therapy (VAC), which yielded a recurrence risk 18% lower when compared
to 33 episodes treated without VAC. In our opinion, the use of VAC for wound closure is always possible when
required, since it does not alter the risk for treatment failure (or remission), provided that there has been a
prior surgical debridement and there is an adequate accompanying, targeted, systemic antibiotic therapy.

Antibiotic Treatment

General Considerations
Antimicrobial agents should be chosen according to the microorganism, the susceptibility profile and the
patient's comorbidities. Table 20.1 shows treatment regimens against the most important microorganisms
causing chronic OM. As long as the causing pathogen is not yet known, the empirical therapy should always
cover S. aureus. However, broad-spectrum initial empirical therapy is not needed, unless the patient is
critically ill or has overt bacteremia. The mechanical surgical debridement is more powerful than the
antimicrobial agent during the first days, while awaiting the microbiological results [44]. Pharmacokinetic
(PK) characteristics of a drug, and the optimal pharmacodynamic (PD) exposure, both in plasma and in the
bone of OM, should be considered for an optimal therapy [45,46] (see Chapter 6), while the estimation of the
antibiotic concentration in bone under daily-life conditions is a difficult task [45, 46]. Of note, the traditional
distinction between bactericidal and bacteriostatic drugs for each individual pathogen is clinically not relevant,
since this particular criterion is not discriminative regarding the outcome in bone and joint infection [47].

Table 20.1. Targeted antibiotic therapy for most common chronic osteomyelitis after surgical
debridement.
 Alternative
Pathogen(s) Initial therapy therapy Oral therapy*

S. aureus (MSSA)
Cefazolin 2 g (IV) Fluoclaxillin 2 g (IV) Rifampin 600 mg qd + Ciproflocaxin
tid 0–2 wks qd 0–2 wks 500 mg bid 4–6 wks

Clindamycin 600 mg tid 4–6 wks

S. aureus (MRSA) Vancomycin 1 g (IV) bid 0–2 wks
Daptomycin 6–8 mg/kg (IV) qd 0–2 wks
Rifampin 600 mg qd 4–6 wks +
Fusidic acid 500 mg tid 4–6 wks
Clindamycin 600 mg tid 4–6 wks (is
susceptible)

Linezolid 600 mg (PO) bid 4–6 wks

Β-hemolytic streptococci Penicillin G (IV) Ceftriaxone 2 (IV) qd Clindamycin 600 mg tid 4–6 wks
6x4 mio. U

Enterobacteriaceae
Ceftriaxone 2g (IV) Ceftazidime 2 g (IV) Ciprofloxacin 750 mg bid for 4-6 wks,
qd, 0–2 wks tid
eventually trimethoprim/
Ertapenem 1 g (IV) Cefepime 2 g (IV) tid sulfamethoxazole
qd, 0–2wks

Gram-negative non-fermenting rods; Ceftazidime 2 g (IV)

e.g. Pseudomonas aeruginosa tid, 0–2 wks Cefepime 2 g (IV) tid Ciprofloxacin 750 mg bid for 4–6 wks

Imipenem/cilastin
(IV) 4 x 0.5 g

Piperacillin/
tazobactam (IV) 4.5 g
tid

Gram-negative anaerobes Co-amoxiclav – Metronidazole 500 mg tid 4–6 wks

4x1.2–2.2 g, 0–2
wks

*
Avoidance of beta-lactam antibiotics for oral therapy (because of moderate oral bioavailability and poor
bone penetration in oral form).

Duration of Systemic Antibiotic Treatment

There is growing evidence in favor of oral antibiotic therapy for OM with selected (i.e. non-beta-lactams)
antimicrobial agents, after a few days of initial intravenous therapy (Table 20.1). In contrast, there are less
publications analyzing the optimal duration of antibiotic therapy [19,36,48–50]. Several case series reported
remission with therapy length of two to four weeks [48], or equal remission incidents with less than six weeks
versus more than six weeks of therapy [51]. One prospective randomized study found no statistically significant
difference in the rates of clinical or microbiological remission rate between patients randomized to four and six
weeks of systemic antibiotics, respectively, for residual OM after complete removal of an infected orthopedic
implant [52]. A recent review targeting the history of antibiotic durations for OM concludes that treatment
durations of less than four weeks are possible in patients with a low clinical risk of recalcitrant disease [53].
However, in patients with a high clinical risk for recurrences (due to obvious co-morbidities), a short duration
might possibly be inadequate.

Local Antibiotic-Releasing Delivery Systems

In chronic OM, there is little clinical evidence concerning the supplementary benefit of the postsurgical
use of local antibiotics in addition to systemic therapy [54]. Theoretically, a local drug concentration up to
1000 times in excess of the MICs (minimal inhibitory concentrations) can be achieved with these systems,
providing high local activity without adverse systemic effects [55]. However, the benefits have not been
unanimously proven. Drawbacks of local administrations are the unpredictable time-dependent drug release
and the potential need for a second surgical intervention to remove the vehicles. Moreover, the risk for
selection of antibiotic-resistant strains increases when the concentration falls below the MIC [56]. This is
a time-dependent event, because local antibiotics are eluted depending on the surface area and the
concentration difference between vehicle and surrounding tissue. Alternatively, the use of absorbable
antibiotic-loaded biocomposites (calcium sulfate; hydroxyapatite) emerged [41]. These synthetic materials are
biodegradable, and therefore a one-staged procedure without secondary removal of the vehicle is possible.
They are osteo-inductive, leading to bone formation and remodeling as the biocomposite dissolves. As an
example, McNally et al. [57] reported primary remission in 96 out of 100 patients, in whom hydroxyapatite
mixed with calcium sulfate and gentamicin has been used in addition to standard treatment. Another new
material under continuous investigation is bioactive glass. It reacts with surrounding tissue to form
hydroxyapatite at the material-tissue-interface, thus creating an osteo-inductive effect. During the process, the
pH of the environment rises, conferring antibacterial properties. In a systematic review on the use of bioglass
in 206 patients with chronic OM, Tanwar et al. [58] reported a remission rate of 86%.

Treatment of Particular Types of Chronic Osteomyelitis in Adults and

Adolescents

Osteomyelitis Associated with Sickle Cell Disease

Sickle cell disease is an autosomal-recessive disorder in the oxygen-carrying hemoglobin molecule in
erythrocytes. It provokes anemia as early as childhood [59]. The disease typically leads to bone necrosis
caused by microvascular occlusion leading to a similar clinical picture as OM [59]. Depending on the continent
the affected child lives on, Staphylococcus aureus plus Salmonella spp. (North America) or Salmonella ssp.
only (West Africa) are the most common pathogens causing OM [59]. Life-time incidence of OM in severe
homozygote disease is estimated at 3% [60]. Treatment is similar to that of classical chronic OM.

Sacral Osteomyelitis
This disease is related to decubitus in patients with multiple comorbidities and/or neurologic disorders.
Failure of reaching remission is most likely, if the reason for chronic OM cannot be reversed. In these patients
with chronic decubitus, the infected sacral bone often cannot be excised. Thus, prevention is of outmost
importance. A thorough daily debridement is the key to success. In improved cases, plastic surgeons may graft
on the exposed bone. Data on the antibiotic management in sacral OM are limited to case series [61]. One
study reported that an antibiotic therapy during less than 6 weeks versus more than 12 weeks had the same
recurrence risk [62]. Furthermore, many patients with chronically exposed bone do not have evidence of OM
when biopsied, and MRI may not accurately distinguish OM from bone remodeling. The goal of therapy should
be local wound care and assessment for the potential of wound closure. If the wound can be closed and OM
is present on bone biopsy, appropriate antibiotic therapy is reasonable. For this goal, actual expert opinion
can even opt for only two weeks of antibiotic therapy [61]. In cases of intractable OM with recurrent septic
episodes, hemicorporectomy is a drastic method of eradication. In a case series of 9 paraplegic patients, the
perioperative complication rate amounted to 100%, and only 4 patients were alive at the last follow-up with an
average survival of 11 years [63].

Outcome of Chronic Osteomyelitis after Treatment

Similar to many orthopedic infections, the risk for recurrence or for a new infection at the same site is around
5–15%; if there is no amputation. Only diabetic foot OM harbors a higher failure risk. While the course of
wound healing provides some information about bone healing, iterative measurements of the serum C-reactive
protein or other markers of inflammation do not [64]. Contrary to implant-related orthopedic infections,
where the academically accepted minimal follow-up duration is two years, there are no standardized minimal
follow-up times for implant-free OM. OM can clinically recur after decades (e.g. in the aftermath of minor
traumas); and even with new pathogens [65]. Therefore, in the judgement of treatment success, the term
“remission” is more appropriate than “cure.”

Key Points

• As a rule, chronic osteomyelitis in adults requires surgical debridement for eradication of bone
infection.
• The recommended duration of concomitant antibiotic therapy is scheduled for roughly six weeks.
• There is no clinical difference in efficacy between oral and intravenous treatment, as long as oral
antibiotics with excellent bioavailability are used.
• Few antibiotic agents reveal a sufficient bone penetration and oral bioavailability for the oral
treatment of chronic osteomyelitis, e.g. clindamycin, linezolid, fluoroquinolones, rifampin.

Acknowledgments
We to thank to the Department of Orthopedic Surgery of Balgrist University Hospital for support.

References
1. Lew DP, Waldvogel FA. Osteomyelitis. Lancet 2004;364:369–379.

2. Metsemakers WJ, Morgenstern M, McNally MA, et al. Fracture-related infection: A consensus on

definition from an international expert group. Injury 2018;49:505–510.

3. Uckay I, Christofilopoulos P. Idiopathic bone marrow oedema with joint effusion: A differential
diagnosis to infectious osteomyelitis. Int J Infect Dis 2019;84:97–98.

4. Greenwood S, Leone A, Cassar-Pullicino VN. SAPHO and recurrent multifocal osteomyelitis. Radiol Clin
North Am 2017;55:1035–1053.

5. Legout L, Assal M, Rohner P, et al. Successful treatment of Candida parapsilosis (fluconazole-resistant)

osteomyelitis with caspofungin in a HIV patient. Scand J Infect Dis 2006;38:728–730.
 6. Papachristou SG, Iosifidis E, Sipsas NV, et al. Management of osteoarticular fungal infections in the
setting of immunodeficiency. Expert Rev Anti Infect Ther 2020;18:461–474.

7. Steinmetz S, Racloz G, Stern R, et al. Treatment challenges associated with bone echinococcosis. J
Antimicrob Chemother 2014;69:821–826.

8. Khurana A, Vardhan A, Negi D. Osteomyelitis variolosa: Forgotten complication of an eradicated

disease. J Clin Orthop Trauma 2019;10:811–815.

9. Lebowitz D, Kressmann B, Gjoni S, et al. Clinical features of anaerobic orthopaedic infections. Infect Dis
(Lond) 2017;49:137–140.

10. Ceroni D, Cherkaoui A, Ferey S, et al. Kingella kingae osteoarticular infections in young children:
clinical features and contribution of a new specific real-time PCR assay to the diagnosis. J Pediatr
Orthop 2010;30:301–304.

11. Ciampolini J, Harding KG. Pathophysiology of chronic bacterial osteomyelitis. Why do antibiotics fail so
often? Postgrad Med J 2000;76:479–483.

12. Uckay I, Pittet D, Vaudaux P, et al. Foreign body infections due to Staphylococcus epidermidis. Ann
Med 2009;41:109–119.

13. Vulin C, Leimer N, Huemer M, et al. Prolonged bacterial lag time results in small colony variants that
represent a sub-population of persisters. Nat Commun 2018;9:4074.

14. Zimmerli W, Sendi P. Orthopaedic biofilm infections. APMIS 2017;125:353–364.

15. Masters EA, Trombetta RP, de Mesy Bentley KL, et al. Evolving concepts in bone infection: redefining
“biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”. Bone
Res 2019;7:20.

16. de Mesy Bentley KL, Trombetta R, Nishitani K, et al. Evidence of Staphylococcus aureus deformation,
proliferation, and migration in canaliculi of live cortical bone in murine models of osteomyelitis. J Bone
Miner Res 2017;32:985–990.

17. Emslie KR, Nade S. Acute hematogenous staphylococcal osteomyelitis. A description of the natural
history in an avian model. Am J Pathol 1983;110:333–345.

18. Beck-Broichsitter BE, Smeets R, Heiland M. Current concepts in pathogenesis of acute and chronic
osteomyelitis. Curr Opin Infect Dis 2015;28:240–245.
19. Uçkay I, Jugun K, Gamulin A, et al. Chronic osteomyelitis. Curr Infect Dis Rep 2012;14:566–575.

20. Govaert GAM, Kuehl R, Atkins BL, et al. Diagnosing fracture-related infection: Current concepts and
recommendations. J Orthop Trauma 2020;34:8–17.

21. Colmenero JD, Morata P, Ruiz-Mesa JD, et al. Multiplex real-time polymerase chain reaction: a
practical approach for rapid diagnosis of tuberculous and brucellar vertebral osteomyelitis. Spine (Phila
Pa 1976) 2010;35:1392–1396.

22. Abgueguen P, Pichard E, Aubry J. Buruli ulcer or Mycobacterium ulcerans infection. Med Mal Infect
2010;40:60–69.

23. Morgenstern M, Kuhl R, Eckardt H, et al. Diagnostic challenges and future perspectives in fracture-
related infection. Injury 2018;49:83–90.

24. Lee YJ, Sadigh S, Mankad K, et al. The imaging of osteomyelitis. Quant Imaging Med Surg
2016;6:184–198.

25. Waibel FWA, Uçkay I, Sairanen K, et al. Diabetic calcaneal osteomyelitis. Infez Med 2019;27:225–238.

26. Pineda C, Espinosa R, Pena A. Radiographic imaging in osteomyelitis: the role of plain radiography,
computed tomography, ultrasonography, magnetic resonance imaging, and scintigraphy. Semin Plast
Surg 2009;23:80–89.

27. Lauri C, Tamminga M, Glaudemans A, et al. Detection of Osteomyelitis in the Diabetic Foot by Imaging
Techniques: A systematic review and meta-analysis comparing MRI, White Blood Cell Scintigraphy, and
FDG-PET. Diabetes Care 2017;40:1111–1120.

28. Kaim A, Ledermann HP, Bongartz G, et al. Chronic post-traumatic osteomyelitis of the lower extremity:
comparison of magnetic resonance imaging and combined bone scintigraphy/immunoscintigraphy with
radiolabelled monoclonal antigranulocyte antibodies. Skeletal Radiol 2000;29:378–386.

29. 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;47:519–527.

30. Palestro CJ, Love C. Nuclear medicine and diabetic foot infections. Semin Nucl Med 2009;39:52–65.

31. Sonmezoglu K, Sonmezoglu M, Halac M, et al. Usefulness of 99mTc-ciprofloxacin (infecton) scan in

diagnosis of chronic orthopedic infections: comparative study with 99mTc-HMPAO leukocyte
scintigraphy. J Nucl Med 2001;42:567–574.
32. Beckles VL, Jones HW, Harrison WJ. Chronic haematogenous osteomyelitis in children: a retrospective
review of 167 patients in Malawi. J Bone Joint Surg Br 2010;92:1138–1143.

33. Parsons B, Strauss E. Surgical management of chronic osteomyelitis. Am J Surg 2004;188:57–66.

34. Cierny G, 3rd, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop
Relat Res 2003:7–24.

35. Papineau LJ, Alfageme A, Dalcourt JP, Pilon L. Chronic osteomyelitis: open excision and grafting after
saucerization. Int Orthop 1979;3:165–176.

36. Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30
years of clinical trials? Int J Infect Dis 2005;9:127–138.

37. Hogan A, Heppert VG, Suda AJ. Osteomyelitis. Arch Orthop Trauma Surg 2013;133:1183–1196.

38. Simpson AH, Deakin M, Latham JM. Chronic osteomyelitis. The effect of the extent of surgical resection
on infection-free survival. J Bone Joint Surg Br 2001;83:403–407.

39. Waibel FWA, Klammer A, Gotschi T, et al. Outcome after surgical treatment of calcaneal osteomyelitis.
Foot Ankle Int 2019;40:562–567.

40. Fitzgerald RH, Jr., Ruttle PE, Arnold PG, et al. Local muscle flaps in the treatment of chronic
osteomyelitis. J Bone Joint Surg Am 1985;67:175–185.

41. Ferguson J, Diefenbeck M, McNally M. Ceramic biocomposites as biodegradable antibiotic carriers in

the treatment of bone infections. J Bone Jt Infect 2017;2:38–51.

42. Buono P, Castus P, Dubois-Ferrière V, et al. Muscular versus non-muscular free flaps for soft tissue
coverage of chronic tibial osteomyelitis. World J Plast Surg 2018;7:294–300.

43. Tan Y, Wang X, Li H, et al. The clinical efficacy of the vacuum-assisted closure therapy in the
management of adult osteomyelitis. Arch Orthop Trauma Surg 2011;131:255–259.

44. Schindler M, Gamulin A, Belaieff W, et al. No need for broad-spectrum empirical antibiotic coverage
after surgical drainage of orthopaedic implant infections. Int Orthop 2013;37:2025–2030.

45. Landersdorfer CB, Bulitta JB, Kinzig M, et al. Penetration of antibacterials into bone: pharmacokinetic,
pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet 2009;48:89–124.
46. Deabate L, Pagani L, Uçkay I. Modern antibiotic treatment of chronic long bone infections in adults-
theory, evidence and practice. Mediterr J Infect Microbes Antimicrob. 2014;3:9.

47. Betz M, Landelle C, Lipsky BA, Uçkay I. Letter to the editor concerning the review of Prof. Sheldon L.
Kaplan “Recent lessons for the management of bone and joint infections”–Bacteriostatic or bactericidal
agents in osteoarticular infections? J Infect 2015;71:144–146.

48. Haidar R, Der Boghossian A, Atiyeh B. Duration of post-surgical antibiotics in chronic osteomyelitis:
empiric or evidence-based? Int J Infect Dis 2010;14:752–758.

49. Scarborough M, Li HK, Rombach I, et al. Oral versus intravenous antibiotics for bone and joint
infections: the OVIVA non-inferiority RCT. Health Technol Assess 2019;23:1–92.

50. Preiss H, Kriechling P, Montrasio G, et al. Oral flucloxacillin for treating osteomyelitis: a narrative
review of clinical practice. J Bone Jt Infect 2020;5:16–24.

51. Rod-Fleury T, Dunkel N, Assal M, et al. Duration of post-surgical antibiotic therapy for adult chronic
osteomyelitis: a single-centre experience. Int Orthop 2011;35:1725–1731.

52. Benkabouche M, Racloz G, Spechbach H, et al. Four versus six weeks of antibiotic therapy for
osteoarticular infections after implant removal: a randomized trial. J Antimicrob Chemother
2019;74:2394–2399.

53. Cortes-Penfield NW, Kulkarni PA. The history of antibiotic treatment of osteomyelitis. Open Forum
Infect Dis 2019;6:181.

54. van Vugt TAG, Arts JJ, Geurts JAP. Antibiotic-loaded polymethylmethacrylate beads and spacers in
treatment of orthopedic infections and the role of biofilm formation. Front Microbiol 2019;10:1626.

55. Kanellakopoulou K, Giamarellos-Bourboulis EJ. Carrier systems for the local delivery of antibiotics in
bone infections. Drugs 2000;59:1223–1232.

56. Streuli JC, Exner GU, Reize CL, et al. In vitro inhibition of coagulase-negative staphylococci by
vancomycin/aminoglycoside-loaded cement spacers. Infection 2006;34:81–86.

57. McNally MA, Ferguson JY, Lau AC, et al. Single-stage treatment of chronic osteomyelitis with a new
absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: a prospective series of
100 cases. Bone Joint J 2016;98b:1289–1296.

58. Tanwar YS, Ferreira N. The role of bioactive glass in the management of chronic osteomyelitis: a
systematic review of literature and current evidence. Infect Dis (Lond) 2020;52:219–226.
 59. Vanderhave KL, Perkins CA, Scannell B, Brighton BK. Orthopaedic manifestations of sickle cell disease.
J Am Acad Orthop Surg 2018;26:94–101.

60. Al-Tawfiq JA. Bacteroides fragilis bacteremia associated with vertebral osteomyelitis in a sickle cell
patient. Intern Med 2008;47:2183–2185.

61. Wong D, Holtom P, Spellberg B. Osteomyelitis complicating sacral pressure ulcers: whether or not to
treat with antibiotic therapy. Clin Infect Dis 2019;68:338–342.

62. Jugun K, Richard JC, Lipsky BA, et al. Factors associated with treatment failure of infected pressure
sores. Ann Surg 2016;264:399–403.

63. Janis JE, Ahmad J, Lemmon JA, et al. A 25-year experience with hemicorporectomy for terminal pelvic
osteomyelitis. Plast Reconstr Surg 2009;124:1165–1176.

64. Uçkay I, Garzoni C, Ferry T, et al. Postoperative serum pro-calcitonin and C-reactive protein levels in
patients with orthopedic infections. Swiss Med Wkly 2010;140:13124.

65. Uçkay I, Assal M, Legout L, et al. Recurrent osteomyelitis caused by infection with different bacterial
strains without obvious source of reinfection. J Clin Microbiol 2006;44:1194–1196.

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