The Foot 27 (2016) 36–40

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The Foot
journal homepage: www.elsevier.com/locate/foot

Case report

Calcium sulphate as a drug delivery system in a deep diabetic

foot infection
Robert Morley ∗ , Felix Lopez, Frank Webb
Department of Podiatric Surgery, Buxton Hospital, London Road, Buxton, Derbyshire SK17 9NJ, United Kingdom

h i g h l i g h t s

• Calcium sulphate as a drug delivery system is an effective adjunct in deep diabetic foot infection.
• Local application produces high antimicrobial concentration at the site of infection.
• When given in isolation local application reduces potential toxicity compared to other routes.
• This method of administration can reduce costs and reduce reliance on patient adherence.

a r t i c l e i n f o a b s t r a c t

Article history: Treating diabetic foot infection is costly, time consuming and challenging for the patient and clinician
Received 17 May 2015 alike. It requires a multidisciplinary approach to provide a favourable outcome but all too often results
Received in revised form 2 July 2015 in amputation.
Accepted 6 July 2015
We present a patient with Type 2 diabetes who attended clinic with a limb threatening foot infection
complicated by osteomyelitis and requiring emergency surgery and antibiotic administration.
Keywords:
Our patient underwent surgery by means of an incision and drainage procedure with local antibi-
Diabetes
otic administration to augment systemic antibiotics. The wound was packed with calcium sulphate
Foot infection
Osteomyelitis
(Stimulan® Biocomposites Ltd.) impregnated with gentamicin and vancomycin to enable high antibi-
Calcium sulphate otic concentrations at the site of infection. The patient made a full recovery at four months requiring only
Antibiotics minimal bone excision to maintain a functional foot.
This case demonstrates an alternative route for antibiotic administration to overcome some of the
limitations of systemic administration including penetration at the site of infection, systemic toxicity,
prolonged hospital admission and cost. This route of administration is being increasingly used as an
alternative to systemic antibiotics at our centre.
© 2015 Elsevier Ltd. All rights reserved.

1. Introduction uncommon [6]. Efficacy of systemic antibiotics may be limited by

impaired blood flow of infected bone [7] and bacterial strains form-
Osteomyelitis is an infective process in bone accompanied by ing biofilms leading to actual or apparent resistance [5,6]. Long term
bone destruction [1] and characterised by substantial morbid- duration and high doses of antibiotics whether parenteral or oral
ity [2]. It presents significant therapeutic difficulties [3] usually are also associated with severe adverse effects [5,6,9] including sys-
requiring a multidisciplinary approach [4] with the goal of treat- temic toxicity with liver and renal impairment [10]. Furthermore
ment to eradicate infection, promote repair of skeletal defects, heal increased costs and lack of patient adherence are further disadvan-
offending wounds and restore function [3,5,6]. Treatment usually tages to long term antimicrobial therapy [6]. Surgical debridement
requires combined surgical debridement and appropriate antimi- meanwhile of non-viable infected bone and soft tissue can leave
crobial therapy [3,7]. large defects resulting in dead space [7] with loss of function.
Systemic antibiotics however are often ineffective [8] even after Local administration of antibiotics have been used as an adjunc-
prolonged intravenous treatment and recurrence of infection is not tive therapy to oral and parenteral antibiotics [4] and in some cases
as a viable alternative [5,6]. Drug delivery systems in the form of
bone void fillers have been shown to produce prolonged high con-
∗ Corresponding author. Tel.: +44 01298 212202; fax: +44 01298 212240. centrations at the site of infection, minimise systemic levels [5,7],
E-mail addresses: robertmorley@nhs.net (R. Morley), AXYH30@dsl.pipex.com eliminate concerns with regards to antibiotic penetration [6] and
(F. Lopez), frankwebb@nhs.net (F. Webb). fill dead space [7].

http://dx.doi.org/10.1016/j.foot.2015.07.002
0958-2592/© 2015 Elsevier Ltd. All rights reserved.
 R. Morley et al. / The Foot 27 (2016) 36–40 37

Fig. 1. Plantar ulcer and source of infection. Fig. 2. Formation of abscess on dorsal surface of the foot.

In this case study we demonstrated the use of a synthetic, Based on clinical and radiographic examination a decision was
biodegradable and biocompatible form of calcium sulphate (CS) made to operate immediately under local anaesthesia via ankle
as a drug delivery system to treat a deep diabetic foot infection blockade. This would involve an incision and drainage, thorough
complicated by osteomyelitis. suction irrigation and packing with CS beads impregnated with
vancomycin and gentamicin.
A longitudinal incision over the second intermetatarsal space of
2. Case report
the left foot was performed to drain the large abscess of copious pus
(Fig. 5). This was followed by sharp and blunt dissection to the third
A 52 year old male patient with Type 2 diabetes of 19 years
metatarsal and proximal phalanx. This revealed soft brown bone
duration with controlled hypertension and hypercholesterolaemia
consistent with devitalised tissue. The base of the proximal phalanx
was referred from the diabetes specialist podiatrist for immediate
and 3 cm of the distal aspect of the third metatarsal were excised
assessment due to a limb threatening foot infection. The diabetol-
back to healthy looking tissue. Soft tissues were examined in the
ogist had counselled the patient with regards to the likelihood of
operative area and excised as necessary and sent to microbiology
amputation.
for culture and sensitivity testing. The plantar ulcer was curetted
The patient presented with an eight month history of recurrent
and a sinus was removed which extended dorsally to the abscess.
plantar ulceration to left foot (Fig. 1) measuring 8 mm × 6 mm and
probing to the third metatarsophalangeal joint. The lesion had dete-
riorated significantly in the last few days with abscess formation
evident both clinically (Fig. 2) and sonographically (Fig. 3). Plain
radiographs demonstrated osteomyelitis of the third metatarsal
head and base of the proximal phalanx (Fig. 4).
The patient felt generally well, there was no pyrexia. However,
further observations demonstrated tachycardia with an elevated
pulse of 106 (60–100) along with elevated random blood glucose
levels of 11 mmols/L. Vascular status revealed bounding biphasic
posterior tibial and dorsalis pedis pulses while neurological testing
demonstrated profound peripheral neuropathy with no ability to
appreciate a 10 g monofilament or vibration sensation within the
foot.
Drug history revealed ramipril, doxasosin, simvastatin and exe-
natide to control comorbidities. The patient was further prescribed
oral ciprofloxacin 750 mg twice daily and clindamycin 600 mg three
times daily for the infection based on previous microbiology results
which identified a polymicrobial infection including Staphylococcus
aureus, group B Streptococcus, Enterococcus faecalis and Pasteurella
multocida. Fig. 3. Ultrasound demonstrating large collection of pus.
38 R. Morley et al. / The Foot 27 (2016) 36–40

Fig. 6. Antibiotic beads packed within the second intermetatarsal space.

placed on crutches and advised to be non weight-bearing. The

patient was reviewed after 24 h following the surgical intervention
(Fig. 7).
Twenty-four hours following surgery the wound was clean with
a degree of erythema reduction.
An MRI had been arranged in-order to determine the extent of
Fig. 4. Plain film demonstrating osteomyelitis of the third metatarsophalangeal osteomyelitis to aid preoperative planning. However, due to the
joint. urgency of the surgery this was not performed until 24 h post-
surgical intervention. The result demonstrated bone oedema in the
remaining portion of the third metatarsal which was reported by
Thorough suction irrigation using 50/50 betadine and saline mix radiology as possible osteomyelitis. This was felt to be more likely
ensued. a consequence of the surgical trauma. However, due to the uncer-
Preparation of the CS bone substitute involved mixing genta- tainty the multidisciplinary team consisting of the diabetologist,
micin in liquid form (3 mL/120 mg) to vancomycin (1 g) in powder microbiologist and podiatric surgeon recommended a commence-
form and 5 ccs of CS hemihydrate. This is subsequently placed in a ment of four weeks of oral linezolid 600 mg twice daily and eight
mould to produce multiple beads. These crystallise and set with the weeks of oral ciprofloxacin 750 mg twice daily. This was based on
liberation of little heat (up to 37 ◦ C) to form CS dihydrate [4,11–13]
or gypsum. Setting time is determined by the time taken for con-
version of hemihydrate to dihydrate [4] which using these doses
and volume of CS is generally 5 min. The final result is a synthetic
biocompatible material acting as a drug delivery system.
The beads were packed into the wound and around the
remaining bone to ensure thorough coverage within the foot
(Fig. 6). The skin edges were apposed with single non absorbable
interrupted sutures and dressed appropriately. The patient was

Fig. 7. A plain film four weeks post-operatively demonstrating residual CS beads in

Fig. 5. Intraoperative photograph showing the ‘milking’ of pus. situ.
 R. Morley et al. / The Foot 27 (2016) 36–40 39

Enterococcus faecalis and Cornyebacterium striatum cultures derived In terms of disadvantages, calcium sulphate does not provide
from the pus and bone samples. The oral route of administration structural support [14] and there is potential for antibiotic losses
also enable discharge from hospital. through wound discharge [10]. In addition, transient cytotoxic
The patient continued to be reviewed twice weekly. Both the effects leading to inflammatory reactions have been observed sus-
plantar ulcer and dorsal surgical wound healed at just over one pected to be calcium rich fluid formed during resorption [13,18].
month and three months respectively and a full recovery was noted This can present as erythema and oedema in the peri-incisional area
at four months. Bespoke footwear was subsequently arranged to accompanied by the release of copious serous discharge from the
accommodate the altered foot pressures. Eleven months following wound [19]. However, in 36 cases performed at our centre we have
the surgery the patient remains healed to date. not experienced any cytotoxic inflammatory reactions following
implantation.
The purity of medical grade CS ensures predictable dissolution
3. Discussion [10] with the beads showing in vivo resorption in three to four
weeks [4]. This also ensures predictable antibiotic release with
The external use of calcium sulphate or plaster of Paris has in vitro elution shown to last 28 days and antibiotic levels sur-
been used since the seventeenth century [14] to splint fractured passing 200 times the minimum inhibitory concentration for an
bones and more latterly by Dreesmann in 1892 who first used it organism over 14 days [6]. Kanellakopoulou et al. [12] meanwhile
as an internal bone defect filler [15]. Medical grade CS belongs demonstrated sustained release of moxifloxacin from CS for 35 days
to a synthetic ceramic group of bone graft substitutes [14] which with greatest release on day seven with complete eradication of
came about in the latter half of the twentieth century following MRSA in animal models with osteomyelitis.
extensive work by Peltier [7]. It was introduced as a biocompatible, Deciding which antibiotic to mix with CS depends on multi-
biodegradable bone graft material [1,5] which has been found to ple factors including likely microorganisms, sensitivities, allergies
be a safe, effective and economically viable [14] which may help and setting times. Various extracts and antibiotics have been
preserve function along with reduction of dead space [1,6,13]. It used previously to help eradicate infection locally including plant
has the longest proven clinical history as a bone graft substitute derived antiseptics [20] moxifloxacin, fucidic acid [3], vancomycin
and widely used in non-loading bone injuries such as radial frac- [3,9,11], tobramycin [5,7,10], gentamicin [2,5,17] and daptomycin
tures [11] to support mechanical stability. It overcomes many of [4]. Aminoglycosides and glycopeptides predominate due to their
the limitations of autograft as a gold standard such as limited sup- broad spectrum, thermostability, kinetic release and efficient
ply, additional surgery, increased tourniquet times and donor site adhesion to the carrier [7,8] ensuring rapid setting times. Amino-
morbidity [14]. glycosides also demonstrate low hypersensitivity and low tissue
CS has also been shown to provide osteoconductive properties toxicity and operate through concentration dependant killing so
[6,11,13] allowing neovascularisation and ingrowth of new bone high local concentrations are favourable [10].
formation [14] further enabling fibrovascular tissue to take its place It was decided in this case that gentamicin and vancomycin
once fully resorbed over which bone can consolidate [14]. Iannuc- would be used due to the aforementioned characteristics of
celli et al. [8] studied 15 cases of bone grafting using CS for various these drugs and on culture and sensitivity results. In addition,
bone defects 13 of which showed new bone incorporation with these have been used in combination on previous occasions with
no incidence of hypercalcaemia or soft tissue calcification. Aseptic favourable results. Rausschmann et al. [13] demonstrated a ten-
serous discharge was found to be the most common complication fold minimum inhibitory concentration of in vitro gentamicin
lasting three to four weeks. We have found that good soft tissue and vancomycin susceptible bacteria within the first 3 and 4
coverage, primary closure and appropriate dressings can help min- days respectively. Gauland [6] meanwhile found this combination
imise this complication. demonstrated a high rate of success despite microbiological sen-
More recently bone defect fillers have been used as antibiotic sitivities and numerous choices for implantation. Three hundred
drug delivery systems. These include non-biodegradable materials and twenty-three patients with osteomyelitis of the lower extrem-
such as acrylic bone cement in the form of polymethyl methacrylate ity underwent surgical debridement and antibiotic implantation of
(PMMA) beads or biodegradable materials such as CS [1,3]. which 70% did not require systemic antibiotics.
Non-biodegradable PMMA beads impregnated with antibiotics One of the most important advantages of local antibiotic admin-
have been used since the early 1970s [10] and are widely accepted istration are the low systemic levels reducing potential toxic
as a major non-biodegradable carrier system to deliver antibiotics reactions and has been demonstrated in numerous studies [5,12]. At
locally [6]. However, they may require further invasive surgery our centre we have previously successfully used antibiotic impreg-
for their removal on completion of drug release [3,5,13] and nated CS as an alternative to systemic antibiotic administration
incomplete and very slow release has been demonstrated [10,11]. where patients have previously developed Clostridium difficile fol-
Furthermore cement polymerisation is an exothermic reaction lowing prolonged courses of antibiotics. Bypassing the digestive
limiting choice to heat stable antibiotics. During hydration of CS system in these patients is clearly advantageous in reducing the
hemihydrate however there is no thermal damage to the drug due potential for further episodes.
to lower curing temperatures. This enables the use of a wider range The prospect of systemic toxicity however following local
of antibiotics including vancomycin, teicoplanin, tobramycin, cefa- implantation should not be overlooked especially in biodegrad-
zolin and fucidin [4]. able materials where all of the antibiotics are likely to be eluted
CS as a drug delivery system was first demonstrated in 1928 [10]. This is particularly pertinent for drugs such as aminogly-
by Petrova who successfully inserted the antiseptic Rivanol into cosides including gentamicin which are known to be exclusively
the long bones of canines [16]. More recently CS has been shown excreted unchanged by glomerular filtration [10] and hence require
to be successful as a controlled drug delivery system in surgical adequate renal function not always evident in the elderly and
prophylaxis as well as in the treatment of acute and chronic soft in patients with diabetic nephropathy. Wahl et al. [10] recom-
tissue and bone infections including the diabetic foot [6,10] and mended aminoglycosides be used with caution in patients with
in the prevention of biofilms [17]. Furthermore the biodegradable low to very low creatinine clearance after examining the pharma-
properties negate the need for further surgical intervention, which cokinetic effects of 4% tobramycin using CS as a carrier material
could otherwise induce further infection and jeopardise bone heal- although no specific values were given. Additionally, serum lev-
ing [1,4,7,9,11]. els were based on predictions and the authors openly admit the
40 R. Morley et al. / The Foot 27 (2016) 36–40

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