Use of local antibiotic depot (stimulan)

Local Antibiotic Delivery by Stimulan
Dr Mangal Parihar

Hon Assistant Prof, Grant Medical College
& JJ Group of Hospitals

Orthopedic Surgeon
Mangal Anand Hospital,
Sir H N Hospital,
Fortis Hospital,
Police Hospital
Mumbai
Center for Limb Lengthening & Reconstruction, Mumbai
www.ilizarov.in

Fully setting paste with individual pelletizing kit

5, 10cc packs!

Mixed for 1-2 minutes to become paste!

Sets in-vivo in 15 minutes at body temperature

T!&!C!Apply!!!

Product summary
First generation calcium sulphates

!
!
• Incidences!of!serous/sterile!drainage!!
13;19%!incidence!in!benign!bone!lesions!(Buckwalter!et!al)!
!Anecdotal!ﬁeld!reports!higher!>!lasGng!up!to!3;5!weeks.!
!
• Mineral!impuriGes;Processed!from!mined!gypsum!rock!

• Acidic!pH!

• Hydrophobic!!

!!

Comparison Table – Competitor Products

Phase analysis Commercial Calcium Medical / Surgical Stimulan® implant
Sulphate Grade Grade

CaSO4 2H2O 80-94%> 98%> 100%

CaCO3MgCO3*!! 5.1% 0.5% Nd

CaCO3 1.0% 0.3% Nd

Aggregate** 4.5% 0.3% Nd

Nd!!!!!!Not!detected!
*!!!!!!!!!The!earth!mineral,!dolomite!
**!!!!!!!!Aggregate!or! earth!impuriGes !are!present!in!calcium!sulphate!sourced!from!!
!!!!!!!!!!!mined!gypsum!rock.!They!are!non;bioabsorbable!and!can!include!such!elements!!
!!!!!!!!!!!as!feldspar,!clay!and!crystalline!silica!(quartz)!

Product summary

Key benefits over Competitor products
!
"   Physiologic pH!
•  Hydrophilic!
•  No traces of potentially toxic impurities!
•  Consistency in clinical performance!
Key Features
!
•  Biocompatible!
•  Fully resorbable – no nidus for bacteria!
•  Sets at body temperature !
•  Pyrogen Free!
•  FDA cleared for use in infected cases

Center for Limb Lengthening & Reconstruction, Mumbai www.ilizarov.in 6

Moxifloxacin Elution
P. Panagopoulos et al. / International Journal of Antimicrobial Agents 32 (2008) 485–487

ns of moxifloxacin were estimated by modifica-
•  MICs
ously described method [4,5] using ciprofloxacin
standard. Briefly, 250 ␮L of sample were diluted

•  MRSA
displacing reagent and centrifuged for 5 min at
splacing reagent consisted of 0.5% sodium dodecyl
(Merck, Darmstadt, Germany) and 20% acetoni-
•  (0.5 - 2 mcg/ml)
75 mM sodium phosphate buffer (pH 7.5). Ten
he supernatant were injected onto an Agilent 1100
formance liquid chromatography (HPLC) system
logies, Waldbronn, Germany) with the following
eristics: Nucleosil® 100-5 C18 (4.6 mm × 250 mm,
under 37 ◦ C; mobile phase consisting of a buffer
sed of 25 mM Na3 PO4 and 10 mM SDS and acetoni-
5/65 ratio with a flow rate of 1 mL/min; ultraviolet
at 293 nm. Ciprofloxacin (Bayer) was added to all
ncentration of 2 ␮g/mL. The retention time of mox-
8 min and its concentration was estimated by a
reated with known concentrations of moxifloxacin.
tion limit was 0.03 ␮g/mL and the interday coeffi-
n of the assay was 0.1%. All determinations were
uplicate.
ns of fusidic for Limb Lengthening & Reconstruction, Mumbaiby
Center
acid were determined in duplicate www.ilizarov.in 7

The calcium sulphate (Stimulan ) commonly used as a bone graft to
of systems for local delivery of moxifloxacin. Collagen shields have
fill bone cavities resulting from disease, trauma or surgery. Its main
the
characteristics are 100% purity and its been applied for its intraocular administration in humans, deliver-
ability for biodegradation.
Moxifloxacin is a fourth-generation quinolone with similar activ- below those described here for StimulanTM
ing concentrations well

Fusidic Acid Elution
ity to that of ciprofloxacin and pefloxacin against Gram-negative repair system was also evaluated as an in
[14,15]. Norian skeletal
bacteria but with enhanced activity against carrier[9]. A recent
vitro MRSA for moxifloxacin by our group [16]. Release lasted for
After almost 400 days but the eluted concentrations were lower than
uted those achieved with StimulanTM as a carrier.
evel The applied carrier in the present study allowed for continuous
d on [
release of fusidic acid lasting for 14 days (Fig. 2). Eluted concentra-
S.D.
was tions over the first 6 days were >100 ␮g/mL and remained above
50 ␮g/mL over most of the period of release. The MIC90 for MRSA [
After is reported to be 0.5 ␮g/mL [17], which makes the developed sys-
uted [
tem of release promising for the eradication of MRSA osteomyelitis.
alue
However, fusidic acid is not a popular candidate for local release
d on [
S.D. systems. Only one study has recently been published where it was
was incorporated in microspheres of poly(lactide-co-glycolide), where [
it proved effective for the management of experimental osteomyeli-
tis caused by MRSA in rats [18].
[
Calcium sulphate has been applied as a carrier in various stud-
ies for the in vitro elution of a variety of antimicrobials, including
cul- vancomycin, teicoplanin, clindamycin, gentamicin and daptomycin
ssue [
[3,19]. Peak elution of all the tested agents was found within the
ents.
has first 2 days. Elution of vancomycin, teicoplanin, clindamycin and
cor- gentamicin lasted only for 10 days, whereas that of daptomycin
[
bone lasted for 28 days. However, released concentrations of daptomycin
TM
d as Fig. 2. Elution of fusidic acid by Stimulan . S.D., standard deviation.
ranged between 5 ␮g/mL and 7 ␮g/mL after Day 4 [19], which are
Center for Limb Lengthening & Reconstruction, Mumbai www.ilizarov.in 8 [

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 2009, p. 3106–3107 Vol. 53, No. 7
0066-4804/09/$08.00ϩ0 doi:10.1128/AAC.01490-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vitro Elution of Daptomycin by a Synthetic Crystallic Semihydrate
Form of Calcium FIG. 1. Elution of daptomycin by Stimulan.
Sulfate, Stimulanᰔ
Kyriaki Kanellakopoulou,1 Periklis Panagopoulos,1 Efthymia Giannitsioti,1 Thomas Tsaganos,1
VOL. 53, 2009 DAPTOMYCIN DELIVERY
Dionyssia-Pinelopi Carrer,1 Nicolas Efstathopoulos,2 and Evangelos J. Giamarellos-Bourboulis1*
4th Department of Internal Medicine1 and 2nd Department of Orthopaedics,2 Medical School, University of Athens, Athens, Greece
study, support the application of the biod
Received 7 November 2008/Returned for modification 28 March 2009/Accepted 17 April 2009
cocci (10). The MICs for 90% of the strains of MRSA,models of o
described here in experimental methi-
cillin-resistant CoNS, and vancomycin-resistant enterococcal
A synthetic crystallic semihydrate form of calcium sulfate, Stimulan, was evaluated as a biodegradable
carrier for the daily in vitro elution of daptomycin. Daptomycin and Stimulan were admixed at a ratio of 95:5.
isolates tested are reported to be 0.78, 0.44, and 0.5 ␮g/ml,
Elution lasted for 28 days. Eluted concentrations peaked on days 1 and 11, when the mean values was 1,320.1
No funding were provided for this study.
and 949.2 ␮g/ml, respectively. The lowest eluted concentration was detected on day 28. These results support
the application of the system described in experimental models of osteomyelitis. None of us has any conflict of interest related
respectively (1, 4). Although the eluted daptomycin concentra-
tions obtained with the system described here are REFERENCES much greater
Chronic osteomyelitis is an infection difficult to treat due prepared. One milliliter of Mueller-Hinton broth (Trec Diag-
1. Baltch, A. L., W. J. Ritz, L. H. Bopp, P. Michelsen,
than the above-mentioned Sussex, United Kingdom)of the strains tested,
both to multidrug resistance of common pathogens and to poor nostic Systems, West MICs for of daptomycin and comparative antimicrob
Activities 90% was added over
penetration of antibiotics into bone (16). Carriers for local
results should the free surface of each mixtureOn each consecutive24 h. The kinetics of
be interpreted with andagainst extracellular and intracellular Staph
bination, replaced every
vials were incubated at 37°C. caution, since in the the

Downloaded from aac.asm.org by on March 17,
delivery of antimicrobials have been developed, attempting to day,
stable small-colony variant human monocyte-deriv
provide locally high concentrations of antibiotics (5). apply to anwas removed,system andsterile plastic tube, andconditions.
release Some eluent in vitro transferred to a not to in vivo
broth. Antimicrob. Agents Chemother. 52:1829–1833
newly developed biodegradable carriers have been shown to be replaced with 1 ml of broth. That procedure was repeated until
2. Cerretani, D., G. Giorgi, P. Fornara,
It should, however, be underscored thatA.eluted2002. The in L. Bocchi, L. cN
very potent for the eradication of experimental osteomyelitis levels are con-
the optical degradation of the prepared mixture. Samples were
ellini, and M. Ritter. vitro elution
(6, 7). The semihydrate form of calcium sulfate (CaSO ), com- stored at Ϫ70°C until analysis.
siderably greater than the concentrations withinimipenem-cilastatin into
4
monly known as plaster of Paris, may be applied as a biode-
mycin combined that are required acrylic
Concentrations of daptomycin were estimated duplicate
gradable system for local drug delivery. It eliminate for macokinetic study. J. Arthroplasty 17:619–626.
has been used the growth of small-colony variants of S. aureus that
by a modification of the method already described (3). Briefly,
decades to fill bone cavities resulting from disease, trauma, or 3. Dandekar, P. K., P. R. Tessier, P. Williams, C. H.
300 ␮l of sample was mixed with 20 ␮l of 99% methanol and
are often implicated in 10 min at Nikolau. 2003. Pharmacodynamic profile of daptom
surgery (11). It was recently shown to be potent in vitro for the centrifuged for chronic bone infections (1).
5,000 rpm and 4°C. Twenty microli-
release of vancomycin, teicoplanin, gentamicin, and clindamy- cus species and methicillin-resistant Staphylococcus a
cin (15). The antimicrobial applied in such an The estimated AUC of elution series; Agilent, Waldbronn, Chemother. 52:405–
infection model. J. considered indirect
may be Antimicrob.
ters of the supernatant was injected into a high-pressure liquid
elution system chromatography system (1100
should be active against the most commonly involved patho- the total amount Hawkey, P. M. 2008. Pre-clinical experience with dap
4.
evidence of Germany) with the following elution characteristics:3):iii7–iii14. AUC
of drug released Zorbax The
a (2).
gens of chronic bone infections, namely, methicillin-resistant Chemother. 62(Suppl. column
Eclipse XDB-C (4.6 by 150 mm, 5 ␮m) separating
for daptomycin by the elution system presentedE.here is much
Staphylococcus aureus (MRSA) and methicillin-resistant coag-
Center for Limb Lengthening & Reconstruction, Mumbai bywww.ilizarov.in
FIG. 1. Elution of daptomycin Stimulan.
8
5. Kanellakopoulou, K., and
(Agilent Technologies) warmed at 37°C, a mobile phase J. Giamarellos-Bourbo
of
ulase-negative staphylococci (CoNS) (5). Daptomycin, which is tems for the local delivery of antibiotics 9 bone inf
in

Antibiotic Elution
•  High Initial Peak
•  Sustained High Local Levels
•  Effectively Sterilise the area upto 3 cm
•  Higher Initial Concentration -
 Higher Peaks and longer period of elution


Advantages

•  Completely Resorbed in 6 weeks
•  2nd surgery for removal not needed
•  No biofilm / membrane produced
•  No Low Level antibiotic release
(resistance?)


Advantages

•  Any Antibiotic
 Thermostable/Thermolabile
 Powder/Liquid
 Combination of 2 or 3 antibiotics
•  Pyrogen Free
•  Pellet form – greater surface area – better
elution

Center for Limb Lengthening & Reconstruction, Mumbai www.ilizarov.in

In contrast, hemi-hydrate calcium sulphate powder has successfully been mixed with either the mixing solution and/or an
antibiotic to achieve full hydration. When the calcium sulphate powder is mixed with a solution or an antibiotic it will become
a paste-like material that will set to a completely hard material. When mixed with the correct quantity of water, it will set

Setting Times and ABs
hard within 8-12 minutes. Between the initial mixing and the complete setting of the paste, the calcium sulphate can be
injected directly into the site or simply moulded by hand into the desired shape.

The effects of commonly used antibiotics on the setting of calcium sulphate
Table 1 - The effects of antibiotics on the setting of calcium sulphate

Amount of calcium sulphate Total Liquid Antibiotic used Mix Mixing Time Setting Time
hemi-hydrate used used / ml and quantity Consistency ± / minutes ± / minutes

10cc 5.6 None Wet 5 9
10cc 5.7 Briklin 1.0g Wet 30 40
10cc 5.6 Gentamycin 0.9g Wet 16 22
10cc 5.9 Zinacef* 1.1g Wet 4 6
10cc 6.2 Flucloxacillin 0.6g Dry 4 6
10cc 5.8 Cefuroxime 3.6ml** Wet 9 13
10cc 6.5 Teicoplanin 400mg† Wet 2 12
10cc 6.5 Vancomycin, 1g Wet 2 12

* Zinacef – 750mg powder + 3ml water ** Cefuroxime – 1.5g powder + 20ml water † Teicoplanin – 400mg powder + 6.5ml water

± All times are approximate, and quantities of antibiotic used do not represent the correct dosage. Dosage of prescription
drugs is the sole responsibility of the operating surgeon.
N.B. for Limb application should be cautious, limiting the total antibiotic load. Dosage should be no higher than one that would
Center Clinical Lengthening & Reconstruction, Mumbai www.ilizarov.in 13

My Experience

•  18 Cases
•  FU 6 - 18 months
•  No continuing infection
•  Single Organism 13
•  Two Organism 5
•  Parenteral Antibiotic - 5 days
 2 cases - 2 weeks
•  Oral Antibiotic 2 weeks

My Experience

•  Osteomyelitis
•  Compound Fractures
•  Bone Void Filling
•  Soft tissue Infections
•  ? Stimulates bone healing


Compound Fracture

•  40 year male
•  Grade II Compound Fracture
•  Delayed presentation
 (24 hrs)


Presentation


Postop


•  Stimulan 10cc
•  Vancomycin 2gm
•  Tobramycin 80mg


4 Weeks - Resorption


7 months


Osteomyelitis


Story So Far…..

•  66 years
•  Discharging sinuses
•  Shortening – 5cm
•  8 years since injury
•  8 surgeries


Nailing


Derotation Plating


Infection, Loosening, Nonunion


Replating, Bone grafting


Re-infection


Ilizarov


Healed


PET Scan


Intraop


Debridement


•  Stimulan 10cc
•  Vancomycin 2gm
•  Both mixing fluids used


Stimulan
Pellets

2 weeks

Dissolution of
Pellets

Sinuses Healed


6 weeks complete resorption


1 year Postop


Septic Arthritis, Non Healing Ulcer

•  38 year
•  Non-Healing Ulcers
•  Discharging sinuses
•  Septic Arthritis Ankle
•  Multi-pronged approach


VAC


Preop


Percutaneous Debridement


Stimulan Paste Injection

Stimulan 10cc + 160mg Tobramycin (Liquid) +
2 Million Units Colistin (Powder)
No Mixing Fluid

Postop Xray

Stimulan Paste

Collagen dressings & Skin
Grafting


Infected NonUnion


Infected Nonunion

•  47 year male
•  Gun Shot Injury
•  Distal Humerus Fracture
•  Infected Nonunion
 – 9 months


2 weeks


6 weeks


Healed


Inadequate Debridement

• Nailing
• Infection
• Antibiotic Rod
• Rod Removed
• Cement left in
• Local Flap


PET CT


Local Antibiotic Delivery
(Vancomycin 2gm
)


Infection - ? Sterilised


August 2011

64

August 2011

65

Plastic Surgeons

•  Cover the Sins of Orthopedic Surgeons
•  Only Delay the Inevitable

7

High Velocity Trauma


Flap Done



•  PRINCIPLES rather than TOOLS
•  Ilizarov ≠ healing
•  Flap & Vascularity ≠ control of infection


The Offender


Old is Gold?


Second Stage - Fixator


August 2011

74

August 2011


Final Healing

76

Final Healing

77

www.ilizarov.in


Use of local antibiotic depot (stimulan)

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