|
|
|
|
Research Article
|
|
Preliminary Clinical Assessment of a Gentamicin-Loaded Monoolein Gel Intended to Treat Chronic Osteomyelitis
|
|
Moustapha Ouedraogo,
Christophe S. Da,
Innocent S. Nacoulma,
Hamado Kafando,
Rasmane Semde,
Issa T. Some,
Rasmata Ouedraogo,
Innocent P. Guissou,
Brigitte Evrard,
Viviane Henschel,
Jacques Dubois
and
Karim Amighi
|
|
|
ABSTRACT
|
The aim of this current study was to perform a preliminary clinical assessment of efficacy and safety of a biodegradable gentamicin-loaded monoolein gel. An open single dose, one treatment study including 19 patients with chronic osteomyelitis caused by a microorganism sensitive to gentamicin was conducted. After surgical curettage of the infected bone, the dead space was filled in with the gentamicin-loaded monoolein gel. To prevent post-operative septicaemia, a systemic antibiotherapy was prescribed for 3 days following the operation. Clinical, biological and radiological follow-up was performed to assess the efficacy and the safety of the treatment. After a follow-up period ranging from 2 to 12 months, all 19 patients included in the study felt well. Eighteen patients recovered from chronic osteomyelitis without adverse events. The wound of one patient whose bone was exposed did not scar over after 10 months. However, it was no longer infected. In conclusion, gentamicin-loaded monoolein gel was efficacious in treating chronic osteomyelitis without side-effects.
|
|
|
|
How
to cite this article:
Moustapha Ouedraogo, Christophe S. Da, Innocent S. Nacoulma, Hamado Kafando, Rasmane Semde, Issa T. Some, Rasmata Ouedraogo, Innocent P. Guissou, Brigitte Evrard, Viviane Henschel, Jacques Dubois and Karim Amighi, 2008. Preliminary Clinical Assessment of a Gentamicin-Loaded Monoolein Gel Intended to Treat Chronic Osteomyelitis. Trends in Medical Research, 3: 82-89. DOI: 10.3923/tmr.2008.82.89 URL: https://scialert.net/abstract/?doi=tmr.2008.82.89
|
|
|
|
|
INTRODUCTION Osteomyelitis is a severe infection of bone and its marrow that
can arise from a variety of mechanisms. Injury (often an open fracture)
and postoperative infection are part of the etiology in the adult patient.
Rarely, adult patients develop osteomyelitis after hematogenous seeding
of long bones during an episode of bacteremia (Parsons and Strauss, 2004).
Osteomyelitis often results in the formation of sequestra or new apposition
of bone (Lew and Waldvogel, 1997). Although empirically understood, there
is no generally accepted definition of chronic osteomyelitis. Numerous
functional definitions have included a variety of criteria: clinical or
radiographic evidence of infection over 6 weeks, relapse or persistence
of infection after appropriate antibiotic therapy and infections associated
with foreign bodies or vascular abnormalities (Parsons and Strauss, 2004).
The chronicity of osteomyelitis is multifactorial. The relative avascular
and ischemic nature of the infected region and sequestrum produce an area
of lowered oxygen tension as well as an area that antibiotics can not
penetrate (Wirganowicz, 1999). Chronic osteomyelitis is a frequent event,
especially in immunocompromised, diabetic, or sickle-cells disease patients (Springer
et al., 2007). It is frequent in Africa and some developing countries.
For example, the frequency of chronic osteomyelitis is about 5% of the
diseases in the orthopaedic and bone surgery Service of Ouagadougou Academic
Hospital/Burkina Faso (Nacoulma et al., 2007).
Gentamicin-impregnated polymethylmethacrylate (PMMA) beads have been
used commonly for many years for the treatment of chronic osteomyelitis.
Local antibiotic concentrations with these beads are clearly higher than
those achieved by intravenous application and they additionally avoid
toxicity resulting from high plasma levels (Sivakuma and Rao, 2002; Mendel
et al., 2005). However, treatment with PMMA beads has some disadvantages.
They are not biodegradable and so a second operation is required to remove
them. To avoid cost, pain and other risks associated with the necessary
second surgical operation for extracting non-biodegradable delivery systems,
biodegradable implants using polymers such as poly (D,L-lactide) or poly
(D,L-lactide-co-glycolide) carriers were investigated (Zhang et al.,
1994). Although these polymeric delivery systems allow prolongation of
the drug release, they are solid, non bioadhesive and often show marked
burst effects due to a high proportion of non-encapsulated drug (Mauduit
et al., 1993; Schmidt et al., 1995).
These limitations of polymeric implants in osteomyelitis management have
led us to develop a gentamicin-loaded monoolein gel. Previous studies
demonstrated that the gel is biodegradable, has suitable physico-chemical
and drug sustained-release properties for use as an implant for the treatment
of chronic osteomyelitis. Biocompatibility and toxicity tests performed
in vitro and in vivo revealed that the gel could be safe
for clinical trial.
The aim of the present study was to evaluate the clinical efficacy and
safety of the gentamicin-loaded monoolein gel we developed.
PROTOCOL The clinical trial of the gel was conducted at the orthopaedic and
bone surgery Service of Ouagadougou Academic Hospital (Burkina Faso).
It was carried out over 12 months (from July 2006 to July 2007).
The Assessed Product The assessed product was a gentamicin-loaded monoolein gel containing
gentamicin sulfate (5%), monoolein (80%) and water (15%). It was a liquid
crystalline gel and became very viscous in contact with aqueous body fluids
at 37°C. The gel was a sustained-release implant. It was sterile and
apyrogenic.
Patient Recruitment Patients admitted to the trial had chronic osteomyelitis. The diagnosis
of osteomyelitis was made on the basis of clinical, biological and radiographic
evidence of infection. A total of 19 patients (16 men and 3 women), aged
from 5 to 50 years old, were recruited. Exclusion criteria included pregnancy
or breast-feeding, severe disease requiring concomitant antimicrobial
therapy, hypersensitivity to aminosides and resistance of the isolated
pathogen to gentamicin. Patients with impaired renal function (serum creatinine
>120 μmol L-1) or with diabetes were also excluded.
Patients received no antibiotic therapy for 7 days before the beginning
of the treatment.
Treatment All patients who were included in the trial received the same treatment
sequence. After a surgical incision, the affected soft and hard tissues
were widely excised. The involucrum was then fenestrated and all the necrotic
bone and sequestra were excised to leave healthy bleeding bone, often
in the shape of a gutter. The dead space was cleaned by sterile normal saline and
filled with the gentamicin-loaded monoolein gel. A suction drain was placed
at the bottom of the gutter. The wound was stitched and packed using iodine
polyvidone-soaked gauzes (Fig. 1). A short course of
antibiotics was prescribed postoperatively. Each patient received intravenous
(IV) gentamicin (at a unique administration of 80 and 160 mg, respectively
for children and adults) and lincomycin (300 and 600 mg every 12 h, respectively
for children and adults) for 3 days after the surgical operation. As an
analgesic, intravenous paracetamol was administered for the 3 first days
at 15 mg kg-1 every 8 h. On the third day after surgical operation,
the suction drain was removed. The surgical wound was cleaned every 3
days with iodine-soaked gauze until healing. Surgical stitches were removed
21 days after the surgical operation.
|
Fig. 1: |
Sequestra removing (a), curettage (b), dead space filling
by the gentamicin-loaded monoolein gel (c) and surgical wound sutured surgical
wound (d) |
Follow-Up and Outcome Isolation and susceptibility to gentamicin of (a) causative pathogen(s)
were obtained before the initiation of therapy. Bacterial culture was
performed if pus occurred. A complete blood count, erythrocyte sedimentation
rate, serum glucose, creatinine, aspartate amino-transferase, alanine
amino-transferase, triglycerides and bilirubins were performed before
the initiation of therapy, on days 5 and 45, then at 3, 6 and 12 months
after the beginning of therapy. Radiographic images of the infected bone
were also obtained at these periods.
Patients were examined clinically for purulent drainage, irritation at
the site of implantation, erythema, local heat, body temperature, diuresis,
auditive acuteness, dizziness and for any adverse event. The clinical
examinations were made twice a week during the first month, then on day
45 and 3, 6 and 12 months after surgical operation. Any serious adverse
event related to the study medication resulted in the patient`s immediate
withdrawal from the study.
Outcomes during the post-treatment follow-up period were classified by
two independent physicians as follows: recovery, defined as the absence
of clinical, biological or radiological evidence of infection throughout
the post-treatment follow-up; improvement, if signs of the infection were
markedly reduced at the end but the wound did not scar over; failures,
defined by the presence of pain, swelling, erythema or purulent wound;
relapse, when a medical event with isolation of the same pyogenic microorganism
from a clinically significant site occurred after healing of the wound.
Ethics The study was conducted in accordance with the principles stated in the
Declaration of Helsinki and approval was obtained from the Ethics committee
for Human health Research of Burkina Faso (No. 2006/016/CERS/BF). Before
starting the study, the patients were informed about the aim and design
of the clinical trial and written consent was obtained.
RESULTS
A total of 19 patients with chronic osteomyelitis were treated.
All patients had infected necrotic bone within a compromised soft tissue
envelope. There were 16 male and 3 female with an age range of 6-50 years
(median 24 years). The duration of their disease ranged from 2 to 11 years
(median 5 years). Before being included in this study, all patients affirmed
that they had previous treatment based on antibiotics by local and/or
systemic route, but without any success. Five pathogen germs were isolated
from the patients with a predominance of Staphylococcus aureus
(Table 1). All pathogens were susceptible to gentamicin. Comorbid disease
(sickle-cell disease with haemoglobin SC) was present in 2 patients. The
White Blood Cell (WBC) levels were normal in all patients except one who
had 12000 WBC mm-3. The hemoglobin concentration in blood ranged
from 9.5 to 13.5 g dL-1 (median, 12.1 g dL-1). The
erythrocyte sedimentation rates at the first and second hour were respectively
over 7 mm (from 15 to 52 mm, median 22 mm) and 13 mm (from 20 to 90 mm,
median 43 mm). Radiographic images showed sequestra in all patients.
The doses of the gentamicin-loaded monoolein gel used to fill dead spaces
ranged from 30 to 110 g (median 55 g) in adults (over 14 years old). With
the two children included in the study, 30 and 70 g of the gel was needed
to fill dead spaces.
Table 1: |
Results of treatment with gentamicin-loaded monoolein gel
in 19 patients with chronic osteomyelitis |
 |
|
Fig. 2: |
Osteomyelitis of a forearm before treatment (a) and 35 days
after treatment (b) with gentamicin-loaded monoolein gel |
All patients were alive and felt well. The quantity of blood in the suction
drain was about 10 mL. Between 6 and 12 days after the surgical operation,
a non-purulent liquid flew along wounds. A bacteriological culture of
this liquid proved that it was sterile. Except for one patient, wounds
of all patients scarred over after between 30 and 70 days (median 42 days)
(Fig. 2, Table 1). The treated bone
of the non-recovered patient was exposed; however, the surgical wound
and bone were neither infected nor purulent. During the biological monitoring
on the 45th day post-operation, erythrocyte sedimentation rates became
normal (below 7 and 13 mm, respectively at the 1st and 2nd hour). Patients
remained apyretic except one who became feverish on day 6 post-operative.
Further investigation demonstrated that this fever was caused by malaria
contracted during the hospitalisation. Administration of quinine enabled
his body temperature to be normalized.
No sign of adverse events was observed. The hemoglobin concentration
had slightly decreased on day 5 post-operative. Serum glucose, creatinine,
aspartate amino-transferase, alanine amino-transferase, triglycerides
and bilirubins values were normal during the follow-up investigations.
Radiographic images showed no sign of bone lesion.
DISCUSSION To the best of our knowledge, this is the first published report
of a clinical trial with a drug-loaded monoolein gel as an implant.
The short course of antibiotics administered intravenously after the
operation aimed to prevent septicaemia from the septic site. The gentamicin-loaded
monoolein gel could take over from these by releasing gentamicin at an
efficacious concentration at the septic site. This therapeutic protocol
was also used by other researchers (Meani and Romano, 1994) to treat chronic
osteomyelitis locally with an antibiotic-impregnated implant, where the
systemic administration of antibiotic lasted 5 days.
The filling of the dead space by the gel prevented haemorrhage at the
surgical operation site; so avoiding post-operative blood transfusion
and constitution of haematoma in the bone. This is one of the advantages
of the assessed gel. Indeed, haematoma does not facilitate sterilisation
of an infectious site (Hall et al., 1983, Fitzgerald et al.,
1985). The mechanism of the haemostatic effect of the gel could be a mechanic
compression of vessels that were damaged during the surgical operation.
The non-purulent and aseptic liquid flowing from the surgical wound (between
days 6 and 12) may have derived from the biodegradation of the gel. Besides,
our previous study of the gel in animal revealed that it was degradable
in vivo.
The clinical, biological and radiological signs in all patients suggested
that the gentamicin-monoolein gel was efficacious in treating chronic
osteomyelitis. The single case of non-recovery (but improvement) could
have been due to the exposure of the treated bone, where there was no
soft tissue to accelerate the skinning. As the bone was not infected after
treatment, skin grafting could be envisaged in this case.
There was no need for long-term systemic antibiotherapy or a second operation
to remove the implanted gel. Therefore, the treatment of chronic osteomyelitis
with the gel was comfortable for the patients. It was also cheap.
Other results from chronic osteomyelitis treatment were obtained with
other therapeutic protocols. The classical treatment of chronic osteomyelitis,
based on both long-term systemic antibiotherapy and surgical debridement,
had failure rates of approximately 25-30% (Blaha et al., 1993;
Nelson et al., 1993). A study (carried out in the orthopaedic and
bone surgery Service where we did our clinical trial) reported that only
33/65 (i.e., 50.8%) patients recovered from chronic osteomyelitis using
long-term (more than 3 months) systemic antibiotherapy (gentamicin and
lincomycin) and surgical debridement without implants. Adverse events
(such as nausea, dizziness, auditive acuteness decrease) to this long-term
systemic administration of antibiotics (which was thus costly and uncomfortable)
were reported. The failure rate of gentamicin-impregnated polymethylmetacrylate
(PMMA) in the local treatment of chronic osteomyelitis was approximately
10-15% (Klemm, 1993; Garvin et al., 1994). It also has the disadvantage
that it is non-degradable and a secondary surgery is required to remove
it after scarring over has occurred (Bucholz et al., 1981; Langlais
et al., 1988; Klemm, 1993; Miclau et al., 1993; Kanellakopoulou
and Giamarellos-Bourboulis, 2000).
The complete blood count, blood chemistry profile and clinical follow-up
confirmed the non-toxicity of the gel at therapeutic doses.
Gentamicin would not be released at a toxic level in the blood, but at
an efficacious dose at the infectious site. Indeed, gentamicin-related
adverse events such as kidney damage, dizziness, auditive acuteness decrease
and minor allergic reactions (Elisenber et al., 1987; Medicines
Complete Browser, 2004) were not observed in any of the patients.
Lack of irritation and bone necrosis at the implantation suggested that
the gel was biocompatible. The lack of adverse events attributable to
the gel was not totally unexpected. All agents (gentamicin, monoolein)
used to make the gel are known to be well tolerated (Ganem-Quintanar et
al., 2000; Rowe et al., 2003).
The safety margin of the assessed gel was large. Doses of gel ranging
from 30 to 110 g were efficacious without provoking damage in adult patients.
It was also efficacious and safe in children at doses ranging from 30
to 70 g.
The follow-up period of maximum 12 months may seem small. However, Waldvogel
et al. (1970) concluded that 95% of recurrences of chronic osteomyelitis
occur within the first 12 months after surgery.
In conclusion, gentamicin-loaded monoolein gel appears to be an effective,
safe and well-tolerated product for the local treatment of patients with
chronic osteomyelitis. The treatment of chronic osteomyelitis with the
gel is expected to be cheap and comfortable for the patients. As the gel
has been shown to be efficacious and safe, in the future multi-centre
randomized controlled trial study including more patients would be conducted
and the period of follow-up extended.
ACKNOWLEDGMENTS The authors would like to thank CUD/CIUF, APEFE and CGRI (Belgium)
for their financial support. We especially thank the patients who volunteered
to participate in this study. The technical help of the orthopaedic and
bone surgery Service (Academic Hospital of Ouagadougou) staff is gratefully
acknowledged.
|
REFERENCES |
1: Blaha, J.D., J.H. Calhoun, C.L. Nelson, S.L. Henry and D. Seligson et al., 1993. Comparaison of the clinical efficacy and tolerance of gentamicin PMMA beads on surgical wire versus combined and systemic therapy for osteomyelitis. Clin. Orthop., 295: 8-12. PubMed | Direct Link |
2: Bucholz, H.V., R.A. Elson, E. Engelbrecht, H. Lodenkamper, J. Rottger and A. Siegel, 1981. Management of deep infection of total hip replacement. J. Bone Joint Surg. (Br.), 63: 342-353. Direct Link |
3: Elisenber, M., H. Koffer, R.A. Glick, M.L. Cornvell and L.E. Loss et al., 1987. What is the cost of nephrotoxicity associated with aminoglycosides? Ann. Int. Med., 107: 900-909. Direct Link |
4: Fitzgerald, R.H., P.E. Ruttle, P.G. Arnold, P.J. Kelly and G.B. Irons, 1985. Local muscle flaps in the treatment of chronic osteomyelitis. J. Bone Joint Surg., 67: 175-185. Direct Link |
5: Ganem-Quintanar, A., D. Quintanar-Guerrero and P. Buri, 2000. Monolein: A review of the pharmaceutical applications. Drug Dev. Ind. Pharm., 26: 809-820. Direct Link |
6: Garvin, K., B. Evans, E. Salvati and B. Branse, 1994. Palacos gentamicin for the treatment of deep periprosthetic hip infection. Clin. Orthop., 298: 97-105. Direct Link |
7: Hall, B.B., R.H. Fitzgerald and J.E. Rosenblatt, 1983. Anaerobic osteomyelitis. J. Bone Joint Surg., 65: 30-35.
8: Kanellakopoulou, K. and E.J. Giamarellos-Bourboulis, 2000. Carrier systems for the local delivery of antibiotics in bone infections. Drugs, 59: 1223-1232. Direct Link |
9: Klemm, K. W., 1993. Antibiotics beads chains. Clin. Orthop., 295: 63-76. Direct Link |
10: Langlais, F., L. Bunetel, A. Segui, N. Sassi and M. Cormier, 1988. Ciments orthopédiques aux antibiotiques. Pharmacocinétique et taux osseux. Rev. Chir. Orthop., 74: 493-503.
11: Lew, D.P. and F.A. Waldvogel, 1997. Osteomyelitis. N. Engl. J. Med., 336: 999-1007. PubMed | Direct Link |
12: Mauduit, J., N. Brukh and M. Vert, 1993. Gentamycin/poly(lactic acid) blends aimed at sustained release local antibiotic therapy administered per-operatively. I. The case of gentamycin base and gentamycin sulfate in poly(D,L-lactic acid) oligomers. J. Control Rel., 23: 209-220. CrossRef |
13: Meani, E. and C. Romano, 1994. Traitement de l'osteomyelite par antibiotherapie locale utilisant une micropompe electronique portable. Rev. Chir. Orthop., 80: 285-290.
14: Medicines Complete Browser, 2004. The Pharmaceutical Press Software. Copyright [c] 2002, (version 1.1.1707.18094). Clinical and Biomedical Computing Limited. Pharmaceutical Press, Cambridge, UK.
15: Mendel, V., H.J. Simanowski, H.C. Scholz and H. Heymann, 2005. Therapy with gentamicin-PMMA beads, gentamicin-collagen sponge and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats. Arch. Orthop. Trauma Surg., 125: 363-368. PubMed | Direct Link |
16: Miclau, T., E. Dahners and R.W. Lindsey, 1993. In vitro pharmacokinetics of antibiotics release from locally implantable materials. J. Orthop. Res., 11: 627-632. PubMed | Direct Link |
17: Nacoulma, S.I., D.D. Ouedraogo, E.W.C. Nacoulma, A. Korsaga and J.Y. Drabo, 2007. Chronic osteomyelitis in University Hospital of Ouagadougou (Burkina Faso). Retrospective study of 102 cases/Ostéomyélites chroniques au CHU de Ouagadougou (Burkina Faso). Etude retrospective de 102 cas (1996-2000). Bull. Soc. Pathol. Exot., 100: 264-268.
18: Nelson, C.L., R.P. Evans, J.D. Blaha, J. Calhoun, S.L. Henry and M.J. Patzakis, 1993. A comparison of gentamicin-impregnated polymethylmethacrylate bead implantation to conventional parenteral antibiotic therapy in infected total hip and knee arthroplasty. Clin. Orthop., 295: 96-101. PubMed | Direct Link |
19: Parsons, B. and E. Strauss, 2004. Surgical management of chronic osteomyelitis. Am. J. Surg., 188: 57-66.
20: Rowe, R.C., P.J. Sheskey and P.J. Weller, 2003. Handbook of Pharmaceutical Excipients. 4th Edn. The Pharmaceuticals Society of Great Britain and the American Pharmaceutical Association, Washington, London.
21: Schmidt, C., R. Wenz, B. Nies and F. Moll, 1995. Antibiotic in vivo/in vitro release, histocompaibility and biodegradation of gentamicin implants based on lactic acid polymers and copolymers. J. Control Rel., 37: 83-94. CrossRef |
22: Sivakuma, M. and K.P. Rao, 2002. In vitro release of ibuprofen and gentamicin from PMMA functional microspheres. J. Biomater. Sci. Polym. Edn., 13: 111-126. PubMed | Direct Link |
23: Springer, I.N., J. Wiltfang, A. Dunsche, G.C. Lier, M. Bartsch and P.H. Warnke et al., 2007. A new method of monitoring osteomyelitis. Int. J. Oral Maxillofac. Surg., 36: 527-532. Direct Link |
24: Waldvogel, F.A., G. Medoff and M. Swartz, 1970. Osteomyelitis: A review of clinical features, therapeutic considerations and unusual aspects. New Eng. J. Med., 282: 198-206. PubMed | Direct Link |
25: Wirganowicz, P.Z., 1999. Aggressive surgical management of chronic osteomyelitis. Univ. Pennsylvania Orthopaedic J., 12: 7-12.
26: Zhang, X., U.P. Wyss, D. Pichora and M.E.A. Goosen, 1994. Biodegradable controlled antibiotic release devices for osteomyelitis: Optimization of release properties. J. Pharm. Pharmacol., 46: 718-724. PubMed | Direct Link |
|
|
|
 |