Evaluating the role of antibiotic-loaded calcium sulphate in the treatment of
chronic osteomyelitis
Jack Carruthers
1. Chronic osteomyelitis overview
4. What are the options?
Aetiology
Haematogenous seeding (rare in West); post-traumatic (especially in compound
fractures); infected foreign body.
Pathology
Bacterial entry into bone triggers an acute inflammatory response. Bacterial
virulence factors disrupt the blood supply, leading to the formation of a necrotic
sequestrum. The infection progresses to chronicity due to damaged skin,
abundant scarring, and impaired vascularity. Patient factors including
malnutrition, diabetes mellitus and smoking contribute to infection persistence.
Infection can spread to the soft tissues causing a discharging sinus.
Clinical features
Localised bone pain accompanied by erythema, and swelling. Sometimes there
are symptoms of systemic infection. A raised ESR and CRP can be present.
Diagnosis
Radiological features include: loss of trabecular architecture, osteopaenia,
scalloping of the inner surface of the bone cortex, periosteal involucrum
formation seen next to a radio-dense sequestrum. (1)
PMMA beads
These were developed by Klemm in the 1970s (4). The delivery of antibiotics
by PMMA bead chains to the osteomyelitic cavity was demonstrated to be in
the order of 200 times that of systemic antibiotics (5). In rabbit experimental
models, treatment of osteomyelitis with PMMA beads showed a 100% success
rate at preventing infection recurrence (6). Human studies by Nelson et al.
demonstrated a reduction in the risk of infection recurrence of 18% in patients
treated with PMMA beads versus conventional therapy (7). PMMA seemed to
be the way forward; but a major concern is that they require a second operation
to remove. Therefore, the focus is now on resorbable antibiotic carriers.
Collagen fleece
Although widely used and biodegradable, collagen fleece has numerous drawbacks. It is associated with seroma formation, and a recent study demonstrated
that it eluted 95% of its gentamicin in the first day (8).
5. Calcium sulphate
2. Current treatment rationale
Chronic osteomyelitis is primarily a surgical disease (2):
• Debride the area of osteomyelitis.
• Take no less than 5 microbiology samples for culture and sensitivity,
and 3-5 histology samples.
• Excise the area of necrotic bone, aiming for healthy bleeding bone at the
cut margins.
• Dead-space management of the cavity, including antibiotic-loaded
carriers.
• Optional muscle flaps can promote revascularisation and healthy bone
formation, and provide soft-tissue coverage of the bone compartment.
• Growth of new bone to fill the cavity can be encouraged by bone
grafting and osteoconductive bone graft substitutes.
Fig. 1. View of calcium sulphate
beads being introduced into a
debrided and excised cavity
(adapted from (13)).
3. Antibiotic-loaded carriers
What? Usually of an inert substance, they are loaded with broad-spectrum
antibiotics and placed into the excision cavity.
Why? They deliver high concentrations of antibiotics locally without the sideeffects of high-dose systemic antibiotics. In addition, they are important
in dead-space management, preventing haematoma formation. The
osteoconductive carriers act as bone graft substitutes, helping new bone
grow to fill the cavity (3).
Fig. 2. View of calcium
sulphate beads on plain Xray before resorption (10).
The first documented use of calcium sulphate, a
bioceramic, to treat bone infections was in 1842 by
Dreesmann (2). Since then, it has been loaded with
antibiotics to create a superior bone graft substitute
and is capable of effective dead-space management:
Antibiotic characteristics
Elution kinetics of many antibiotics, including
gentamicin, were investigated by Wichelhaus et al.
Calcium sulphate releases antibiotic over 10 days or
more in amounts well above the MIC of most
bacteria (9). It provides high local antibiotic
concentrations without systemic side-effects (10).
Resorbable
A prospective study into calcium sulphate pellet
treatment showed full resorption by 6 months posttreatment (10). This obviates the need for a second
operation to remove the dead-space filler.
Osteoconductivity
Immunofluorescence studies demonstrated that both osteoblasts and osteoclasts
could adhere to a calcium sulphate scaffold (11). Chang showed that patients
achieved full weight bearing status 3 months post-treatment for chronic
osteomyelitis, suggesting sufficient bone in-growth (12). Recently,
Franceschini et al. used X-rays 12 months post-op to show that calcium
sulphate Herafill beads, used at the NOC, provide support for undisturbed reossification of the tibia, proving it to be an effective bone graft substitute (13).
Infection control
In goat-models of tibial chronic osteomyelitis, tobramycin-impregnated
calcium sulphate beads loaded into the dead-space prevented recurrence of
infection in 12/12 goats, a figure superior to goats treated with PMMA beads or
control (14). These results were supported by a similar study in rabbits (15).
Studies in humans in Zaire have demonstrated that calcium sulphate is effective
in preventing recurrence of infection (16).
6. Are there other suitable bioceramics?
Current research into bioceramics including calcium sulphate have aimed to
optimise their osteoconductivity. Options other than calcium sulphate include
tricalcium phosphate (TCP) and silicated calcium phosphate (Si-CaP). A
comparative study by Hing et al. showed that calcium sulphate is resorbed too
quickly to provide a smooth continuum between resorption and adsorption of
bone. Indeed, the osteoconductive kinetics of Si-CaP were superior,
demonstrating re-vascularisation and bone apposition over 3-6 weeks (17).
7. Caveats to calcium sulphate use
The limits of osteoconductivity?
The osteoconductivity of calcium sulphate has been called into question in a
number of studies, not least Hing et al. Stubbs showed that while calcium
sulphate provided support for some bone in-growth, it did not result in complete
filling of the defect before total resorption (18). Moreover, the pattern of bone
in-growth in calcium sulphate is sporadic rather than gradual.
Inflammation?
High rates of resorption may result in microparticle-induced inflammation. The
resulting acidic environment favours osteoclast action and further degradation
of the ceramic (19). However, numerous studies challenge this contention, and
anecdotally, the NOC has not encountered this problem.
8. Conclusions: the future
Calcium sulphate fulfils the primary goal for the treatment of any disease:
patient satisfaction. Ultimately, it is a tool which allows patients to achieve an
infection-free fully functional bone or joint.
Calcium sulphate can only be improved. Recent experiments have combined
calcium sulphate with hydroxyapatite (HA) to improve biocompatibility and
osteoconductivity. Both Stubbs et al. and Rauschmann et al. highlighted
superior bone graft properties in calcium sulphate-HA composite carriers (18,
20). Adding a silicon component could enhance its ability to stimulate bone
metabolism (17).Combining calcium sulphate with mesenchymal stem cells to
promote new bone formation and stem cell osteogenic differentiation may be
the next step (21).
9. References
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
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