WO2024256638A1

WO2024256638A1 - Novel method employing antibiotics with accretion to apatite coated implants preventing bacterial attachment and infection

Info

Publication number: WO2024256638A1
Application number: PCT/EP2024/066563
Authority: WO
Inventors: Lars Lidgren; Deepak Raina; Magnus TÄGIL
Original assignee: Moroxite Ab
Priority date: 2023-06-15
Filing date: 2024-06-14
Publication date: 2024-12-19

Abstract

Present invention relates to a novel and effective administration regimen in preventing and/or treating bacterial infection and a novel device.

Description

Novel method employing antibiotics with accretion to apatite coated implants preventing bacterial attachment and infection

TECHNICAL FIELD

Present invention relates to a novel regimen preventing or reducing the occurrence of infection in implant surgery. Specifically, present invention relates to a novel and improved treatment regimen comprising the administration of an antibiotic prior or perioperatively in relation to implanting e.g. an implant of any suitable material into the body of a subject. In one aspect, the implant may be coated with an apatite material, wherein the administered antibiotic, has an affinity for the material The inventors of present invention have surprisingly found that the method of administration of specific antibiotics to a coated implant is essential to prevent bacterial attachment and thereby hinder the device from become infected.

BACKGROUND ART

Thin hydroxyl apatite (HA) coatings of a few micrometers to a few hundred micrometers is commonly applied to orthopedic implant surfaces to enhance their interaction with native bone and thereby increase the anchorage of the implant to the host bone bed. The process of implantation is carried out in a sterile environment with high hygiene standards. Both pre- and post-implantation, patients are given systemically administered antibiotics. Despite antiseptic and sterile measures and a rigorous antibiotic regimen about 1-3% implants get infected and require a reoperation. The numbers might not appear alarming at the first sight but considering the sheer volume of joint replacement worldwide (6 million/year), 60000-180000 patients require revision surgery. Apart from increased morbidity for the patient, revision surgery is estimated to cost 3-times more than the primary surgery and therefore considered a huge healthcare burden. In addition, apatite coated dental implants and fracture devices contributes to the burden of deep infection.

In the case of acute periprosthetic infections, only a few bacteria may attach to the surface of the implant initially when the surgery is completed. Due to lack of antibiotic affinity to HA, these few bacteria may manage to rapidly divide and thereby form biofilms that are very challenging to treat without additional surgery. In the example of hip replacements, Prosthetic Joint infection (PJI) is a devastating complication. Due to the formation of bacterial biofilms, microbes at the implant surface are protected against antibiotics and hampered by emerging antimicrobial resistance. Therefore, there is an urgent need for improved and novel alternatives in preventing PJI especially in uncemented implants.

As mentioned above, hydroxyl apatite/Calcium phosphates are ceramic materials similar to the mineral component of human bone. They are used as implant coatings, moldable putties or injectable drug delivery devices or vehicles.

Orthopedics is the medical speciality with the biggest repair workshop today. In the US and Europe, one out of five retired citizens has a joint prosthesis and it is estimated that 50 % of women will be treated for a fragility fracture. When total hip surgery was introduced in the late 60, one out of 10 got a deep infection. Ground breaking studies by orthopaedic surgeons and bacteriologist in Lund/Malmb reported randomized studies on systemic antibiotic prophylaxis resulting in significant reduction of prosthetic joint infection (PJI). The current standard is giving a cephalosporin one hour prior to arthroplasty surgery in order to have maximal tissue concentration during surgery but cephalosporins have no specific accretion to apatite coated implant.

Deep bone and joint infections (DBJ I) however still constitute a significant and costly societal burden. Whether caused by trauma, tumour surgery or joint replacement, DBJIs require repeated invasive surgery and extensive systemic antimicrobial treatment that can last for years. In addition to potentially serious side effects, aggressive long term systemic antibiotic treatments contribute to emerging bacterial resistance. The ongoing demographic changes in an ageing world have an impact on healthcare with 10 million artificial joints now being inserted yearly and the numbers are on a steep incline. The most feared early complication is deep PJI, which occurs in 1-2 % of patients who undergo joint replacement. As the typical patient tends to be an older individual with substantial comorbidity, an infection often results in prolonged and repeated surgeries, secondary complications, chronic morbidity, and even mortality related to the systemic antibiotic treatment and immobilization. From a cost perspective, the increased direct cost for a patient with an PJI is 5-7 times higher than for a primary procedure corresponding to an additional 50,000 USD per patient in direct cost only. Substantial suffering and resources could be saved if we were be able to prevent DBJIs more efficiently.

DBJIs are directly intertwined with health, demographic change and wellbeing. Although certain groups are heavily affected (e.g., cancer and trauma), older adults are particularly vulnerable as they are more prone to get infections. Post-injury infection rates vary from 1.5 to 33% depending on the severity of the injury. The direct and/or indirect consequences of DBJIs such as pain, reduced health related quality of life (QoL), morbidity, sick leave and premature retirement due to disability place significant burdens on already strained healthcare systems and societal budgets. Emerging bacterial resistance poses a major threat and new innovative treatment modalities are urgently warranted to curb the ongoing trajectory

For optimal efficacy of an antimicrobial surgical prophylaxis treatment, inhibitory concentrations must be achieved in tissue at the time of incision and last during the entire procedure. This has yet to be achieved when revising infected implants. Moreover, replacing infected joint implants is often demanding and time-consuming and reoccurrence of recalcitrant bacteria causing infection occurs in up to 25% of the patients and a longer local antibiotic protection is necessary. In noninfected revisions infection rates close to 10 % have been reported if not extended systemic antibiotic prophylaxis is used. This clearly indicates that accretion to an apatite coated implant with a binding antibiotic resulting in extended bacterial efficacy is important.

A number of antiseptic principles have been introduced in join prosthetic surgery to mitigate endogenous PJI. To avoid exogenous contamination, we use aseptic routines hindering mainly airborne bacteria carried by micro and nano particles from ending up on a joint implant. Air in the operating room is recirculated at 2 m³/s trough HEPA filter (SS-ISO 29463) eliminating 99,7 % of all particles and bacteria. The number of bacterial colonies on a culture plate is given as Colony Forming Units (CFU). An accepted level in joint implant surgery is <10 CFU/m³ which means that an implant still will have a few bacteria on the surface at the end of an operation. The bacteria then start very rapidly within hours to multiply and form colonies protected by developing a biofilm.

The problems associated with bacterial biofilm formation have been underestimated. Microorganisms mature into a biofilm that defies the antibiotics and the body’s own immune defence. Implant manufacturers have been working on antibacterial or antiseptic surface treatment of the implant (i.e. coatings) for the last two decades. In recent years, promising approaches of antibacterial coatings have been developed. However, there are only limited evidence-based practical applications. Meaningful in-vivo data are still scarce, especially from randomized control trials. Endo prosthetic reconstruction after resection of large bone tumour is among the groups with the highest documented infection risk of 10-30%.

Presently, the two main ways of anchoring a joint implant, which are significantly different from each other;

1. Using a Polymethyl methacrylate (PMMA) in the bone bed that aids in distributing load, or 2. More recently, non-cemented (i.e. without PMMA) hydroxylapatite/calcium phosphate coated joint implant.

In case of PMMA, very often the PMMA material contains an antibiotic either gentamycin or tobramycin which has proven effective reducing PJI in combination with systemic antibiotics.

Present invention provides a solution to the above problems in apatite coated implants by eliminating or reducing bacterial loading on an implant and the occurrence of post operative infection.

SUMMARY OF THE INVENTION

Present invention relates to one or more antibiotics with accretion to apatite coated implants for use in the prevention of a bacterial infection. The invention particularly relates to prevention or elimination of the risk of infection in relation to implants.

Present invention also relates to a method of preventing or reducing the reoccurrence of a bacterial infection in relation to an implant.

Present invention also relates to an implant or medical device suitable to be implanted into the body of a subject in need thereof. The implant or device may be coated with a suitable material wherein the material in the coating is characterised by displaying a strong binding to the one or more antibiotics.

In a further aspect, present invention also relates to a novel regimen, wherein one or more soluble antibiotics are administered to an implant prior to surgery achieving effective antibiotic accretion into the multilayer particulate apatite coating resulting in extended bacterial eradicating efficacy.

In a further aspect, present invention also relates to an additional administration, loading and reloading regimen, wherein the one or more antibiotics with accretion to apatite are administered to the subject in a time-dependent manner.

Furthermore, present invention relates to a method of treating a subject or use of one or more antibiotics for eliminating or reducing the risk of bacterial infection in relation to implant surgery, the method or use comprising: a) Optionally, administering one or more antibiotics to an implant or device prior to implantation into the body of the subject, b) In one aspect, the implant or device is coated with an apatite/phosphate material for which one or more antibiotics have a high accretion, c) implanting the device or implant into the body of the subject, wherein optionally, the implant or device is coated with an apatite/phosphate material for which one or more antibiotics have a high accretion or displays a high affinity to, d) optionally systemically administering one or more apatite binding antibiotics to the subject after completion of implantation surgery.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates that TET (tetracycline) pre-treated HA (hydroxyapatite) coated metal implant is protected against bacterial infection in-vitro.

Figure 2 illustrates the effect of serum exposure of HA particles on TET-HA binding as a function of HA particle size and time.

Figure 3 illustrates HA coated metal implants placed in the proximal tibia of rats for 4-7 days followed by TET administration protects the HA coated implant from bacterial colonization. Notice the lack of zone of inhibition when no TET is used. Likewise, if the implant is not coated with HA and TET is administered, the implant cannot be protected thereby signifying the role of HA in attracting TET and consequently protecting the implant.

Figure 4 illustrates the scanning electron micrographs of the harvested implants after one day of culture with S. aureus after the completion of Kirby Bauer disk diffusion test above. It should be noted that when TET is not administered systemically, the bacterial come close to the surface of the implant rapidly and cover the entire surface of the implant. When TET is administered systemically, TET binds to the HA coating on the implant thereby protecting the implant from bacterial colonization. Image was acquired at 2000 x magnification.

Figure 5 illustrates that the timing of TET administration is critical in protecting a HA coated implant from bacterial colonization. HA coated metal implants placed in the proximal tibia of rats. TET was administered either peri-operatively or 5 days post-implantation and either as a single dose or three repeated doses injected 24 h apart.

Figure 6 illustrates representative pictures from the disk diffusion assay performed with GEN loaded HA coated pins. The experiment was performed with at least 2 pins for each concentration and each day. Figure 7 illustrates the measurement of the ZOI using the images obtained from the disk diffusion assay above in Figure 6.

Figure 8 illustrates representative pictures from the disk diffusion assay performed with RIF loaded HA coated pins. The experiment was performed with at least 2 pins for each concentration and each day.

Figure 9 illustrates the measurement of the ZOI using the images obtained from the disk diffusion assay above in Figure 8

Figure 10 illustrates representative pictures from the disk diffusion assay performed with TET loaded HA coated pins. The experiment was performed with at least 2 pins for each concentration and each day.

Figure 11 illustrates the measurement of the ZOI using the images obtained from the disk diffusion assay above in Figure 10.

DETAILED DESCRIPTION

As mentioned herein, present invention relates to i.a. a novel and effective administration regimen. Present invention provides for a more effective reduction or prevention of bacterial infection in relation to implants. Consequently, present invention may also provide for a reduced risk of antibiotic resistance in certain bacterial strains as a more effective treatment of the infection or prevention of occurrence of infection reduced the need for repeated administrations of antibiotics.

In a further aspect, present invention relates to an implant. The implant may be configured to be suitable as an implant into the body of an animal or a human being. In another aspect, the implant may be coated with a particulate material.

In yet a further aspect, the implant may be coated with a particulate material and may further comprise one or more antibiotic compounds.

In one aspect, present invention relates to one or more antibiotic compounds for use in elimination, or reduction, or prevention of bacterial infection that may occur in relation to implant surgery.

Specifically, present invention relates to one or more antibiotic compounds for use in elimination, or reduction, or prevention of bacterial infection in relation to implant surgery, wherein a) optionally, one or more antibiotic compounds are administered to a subject prior to implant surgery is imminent, b) performing surgery whereby a device or implant is placed or otherwise inserted into the body of the subject, wherein the device or implant is coated with a material for which the one or more antibiotics have an affinity or accretion to the coating material, c) administering one or more antibiotic compounds to a subject within a period of 24h or less after surgery.

In one aspect, the device or implant may be coated with a finely divided particulate material.

According to the invention, a “device” or “implant”, which is herein used interchangeably unless otherwise noted, is intended to mean any type of object suitable to be placed or otherwise inserted into the body of a subject. The tissue into which the implant or device may be implanted or inserted may be into any type of tissue such as e.g. soft tissue, bone tissue, or cartilage tissue, or may be suitable to be placed at a location in the body of the subject such that the device or implant is in contact with one or more of soft tissue, bone tissue, or cartilage tissue, muscle tissue etc. The implant or device may be made of any material or mixture of materials suitable to be implanted into the body of a subject. Such material may be any type of plastic/polymeric material, composite material or any type of metal, elastomers or any type of alloys or any combination thereof. One non-limiting example of a metal may be e.g. titanium (Ti). The implant may e.g. be suitable for hip or joint replacement etc. In another aspect, the implant may be in form of a screw or a pin. The screw of pin may be hollow and may optionally comprise a number of fenestrations. Other non-limiting examples are e.g. catheters, spinal cage, any grid or net-like construction, tubes of any kind, stents etc.

According to the invention, the implant may be at least partly coated with a finely divided particulate material. In one aspect, this material may be hydroxyapatite (HA) or calcium phosphate (CaP) in any configuration or crystal structure. Merely for sake of completion, hydroxyapatite which may also be referred to as hydroxylapatite, has the formula Cas(PO4)3(OH), but may also be written as Caio(P04)e(OH)2 to denote that the crystal unit cell comprises two entities. In another aspect, calcium phosphate may be a salt comprising Ca²⁺ combined with either of POr³, HPO2"⁴, or H2PO"⁴. Other non-limiting examples are monocalcium phosphate (Ca(H2PO4)2 and Ca(H2PO4)2(H2O), or dicalcium phosphate (CaHPO4(H2O)2 or CaHPO4(H2O)), or tricalcium phosphate (Cas(PO4)2), or octacalcium phospahate (CasH2(PO4)6-5H2O). In another aspect, CaP may be intended to mean amorphous calcium phosphate which is a glassy precipitate of variable composition that may be present in biological systems. These entities may be denoted or abbreviated as “HA” in present text. The implant or device may be at least partially coated with the particulate material. According to the invention, the particulate material may in principle be in any sizerange.

In one aspect, the particle sizes of the particulate material according to the invention may be in range of microparticles or nanoparticles, or a combination thereof. Consequently, the particle size is preferably e.g. less than 200 pm, such as less than 100 pm, less than 50 pm, less than 35 pm, less than 20 pm or less than 10 pm. Moreover, the particles may be between about 0.1 and about 50 pm. In another aspect the microparticles may be in range of about 1 pm to about 500 pm, such as .e.g about 1 pm to about 100 pm, about 1 pm to about 50 pm, about 1 pm to about 25 pm, about 1 pm to about 15 pm, about 1 pm to about 10 pm, or about 1 pm, about 5 pm, about 10 pm, about 15 pm, about 20 pm, about 25 pm, about 30 pm, about 35 pm, about 40 pm, about 45 pm, about 50 pm, about 75 pm, about 100 pm, about 500 pm etc.

In a particular aspect, the particles of the particulate material may be in size range of e.g. about 1 pm to about 10 pm.

In one aspect, the particles of the particulate material is in size range of e.g. about 0.5 pm to about 50 pm.

In a further aspect, the particles of the particulate material may be in size range of e.g. about 1 .0 pm to about 50 pm.

In one aspect, the particles of the particulate material may be in size range of e.g. about 1 pm to about 25 pm.

In a further aspect, the particulate material may be in size range of e.g. about 15 pm to about 50 pm, of which about 50% of the particles has a size of about 30 pm.

As implied above, the particle size of the particulate material may also be range of e.g. about 1 nm to about 200 nanometres (nm), such as e.g. less than about 150 nm, less than about 100 nm, less than about 50 nm, less than about 45 nm, less than about 40 nm, less than 35 nm, less than about 30 nm, less than about 25 nm, less than about 20 nm, less than about 15 nm, or less than about 10 nm. In one aspect the particle size is in range of e.g. about 1 nm to about 100 nm. In a further aspect, the particles of the first material may be about 1 nm, such as e.g. 5 nm, such as e.g. about 10 nm, such as e.g. about 15 nm, such as e.g. about 20 nm, such as e.g. about 25 nm, such as e.g. about 30 nm, such as e.g. about 35 nm, such as e.g. about 40 nm, such as e.g. about 45 nm, such as e.g. about 50 nm, such as e.g. about 100 nm, such as e.g. about 150 nm, or such as e.g. about 200 nm. In one aspect, the particle size of the particulate material may be in range of about 40 nm to about 100 nm.

In a further aspect, the particle size may be in range of 10 nm to about 50 nm.

In yet a further aspect, the particle size may be in range of about 50 nm, or less than 50 nm.

As also implied above, the particle size may be a combination of micro-sized and nano-sized particles. In one aspect, the mixture of particles may be any combination of about 1 pm to about 500 pm, such as .e.g about 1 pm to about 100 pm, about 1 pm to about 50 pm, about 1 pm to about 25 pm, about 1 pm to about 15 pm, about 1 pm to about 10 pm, or about 1 pm, about 5 pm, about 10 pm, about 15 pm, about 20 pm, about 25 pm, about 30 pm, about 35 pm, about 40 pm, about 45 pm, about 50 pm, about 75 pm, about 100 pm, about 500 pm etc, and/or particles in the range of e.g. 1 and 200 nanometres (nm), such as e.g. less than 100 nm, less than 50 nm, less than 35 nm, less than 20 nm or less than 10 nm. In one aspect the particle size is in range of e.g. about 100 nm to about 1 nm.

In a particular aspect, the particle sizes may be a combination of about 1 pm to about 500 pm, or about 1 pm to about 10 pm, and wherein the nano-sized particles may be in range of about 1 nm to about 200 nm, or about 40 nm to about 100 nm.

In a further aspect, the micro-sized particles may be in range of about 1 pm to about 500 pm, or about 1 pm to about 10 pm, and the nano-sized particles may be in range of about 1 nm to about 200 nm, or about 40 nm to about 100 nm and thus a mixture of the two particle sizes. In another aspect a further aspect, the mixture of nano-sized particles and micro-sized particles may be micro-sized particles may be in range of about 1 pm to about 500 pm, or about 1 pm to about 10 pm, and wherein the nano-sized particles may be in range of about 1 nm to about 200 nm, or about 40 nm to about 100 nm, or about 10 nm to about 50 nm.

In yet a further aspect, the micro-sized particles may be in range of about 1 pm to about 50 pm, and the nano-sized particles may be in range of about 1 nm to about 50 nm, or about 50 nm and thus a mixture of the two particle sizes.

Present invention also relates to the use of one or more antibiotics. In principle, the antibiotic may be any agent displaying a binding affinity towards, or accretion to the particulate material.

Non-limiting examples may be e.g. the antibiotic may be a tetracycline of any kind, such as e.g. tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, tigecycline, omadacycline, sarecyclin or any combinations thereof. In one particular aspect, the antibiotic may be e.g. tetracycline.

Further examples of antibiotics may be any type of antibiotic with a chelating ability towards calcium. This may be in any configuration of a molecule wherein a hydroxyl or amino or phosphonate group are arranged in a vicinal or isolated configuration within the molecule of the antibiotic.

Yet further examples may be e.g. ansamycins. Non-limiting examples thereof are e.g. rifamycins and in particular rifampicin.

Other examples aregeldanamycin, herbimycin A, macbecin, natalamycin, streptovaricin or rifamycins in general or any derivatives thereof.

The antibiotic compound may also be a daptomycin.

The same or different antibiotics may be employed at different times of administering the antibiotic to the subject. In another aspect, a mixture of antibiotics may be employed in one administration.

In one aspect, the antibiotic present in the coating of the implant or device may be the same or different as the antibiotic administered prior to surgery, or post-surgery, or the antibiotic administered during surgery.

In yet a further aspect, the antibiotic present in the coating of the implant or device may also be an antibiotic with little or no affinity to the coating material. A non-limiting example may be e.g. gentamicin.

As mentioned herein, the implant or device may be at least partially coated with the particulate material or may comprise at least partially the particulate material. In the instance of a coating, the coating may be of any suitable thickness, such as e.g. in range of about 0.5 pm to about 1000 pm, or about 1 pm to about 500 pm, such as .e.g about 1 pm to about 100 pm, about 1 pm to about 50 pm, about 1 pm to about 25 pm, about 1 pm to about 15 pm, about 1 pm to about 10 pm, or about 1 pm, about 5 pm, about 10 pm, about 15 pm, about 20 pm, about 25 pm, about 30 pm, about 35 pm, about 40 pm, about 45 pm, about 50 pm, about 75 pm, about 100 pm, about 500 pm etc. In a particular aspect, the thickness of the coating may be about 1 pm to about 50 pm, or 5 pm to about 50 pm, or about 10 pm to about 45 pm etc.

In a further aspect, the thickness of the coating may be in range of about 15 pm to about 40 pm. In another aspect, the thickness of the coating may be in range of about 50 pm to about 200 pm.

In a further aspect, the thickness of the coating may be in range of about 50 pm to about 150 pm.

In yet a further aspect, the thickness of the coating may be in range of about 50 pm to about 100 pm.

In another aspect, the implant or device may at least partially comprise the coating material, i.e. not only as a coating but as a part of the implant or device itself.

In one aspect, optionally, the coated implant may be soaked or impregnated with the one or more antibiotics prior to being implanted into the subject. Such pre-soaking or impregnation may take place by any suitable method such as for example dipping the coated implant or device in a solution comprising the relevant antibiotic compound. In a further aspect, such impregnation or pre-soaking of the device or implant may take place within a few hours before or directly before the surgical procedure.

According to the invention, the timing of administration of the one or more antibiotics is critical. Without being bound to any theory, it is believed that once the surgery has been completed and the implant has been placed into the body of the subject, the particulate material coated onto the implant may be colonized by bacteria which may form a biofilm covering the coating. Another possible event is that the coated implant binds serum or other protein components present in the systemic circulation. The formation of bacterial biofilm and/or serum and protein binding of the particulate material may hinder or otherwise hamper the action of any administered antibiotic. Formulated in another way, the surface of the particulate material becomes passivated by bacterial colonization and/or serum or protein binding, or otherwise, the surface of the implant or device is covered by a thin layer of biological macromolecules and making the surface less accessible to the one or more antibiotics. The inventors of present invention have surprisingly found that some classes of antibiotics bind to and consequently have a strong affinity towards, or accretion to the particulate material, and in particular bind to hydroxyapatite. However, the inventors have also found that administering such antibiotics at a certain time after surgery will largely be ineffective, while administration perioperatively is more effective and crucial for an effective and successful treatment.

In the context of present invention, the term “perioperative” or “perioperatively” is intended to mean that an event takes place in the relative immediacy of the surgery itself. Consequently, said terminology may comprise the point/timing of administration of the one or more antibiotics. However, present invention also relates to administration of the one or more antibiotics pre- operatively, and/or peri-operatively (in this aspect intended to mean during surgery), and/or post-operatively. Thus, the administration of one or more antibiotics may be prior surgery, or after surgery or both prior and after surgery. In one aspect, the administration of the one or more antibiotics may take place one or more times within the time span of about 24 h before the operation, and/or during the operation itself, and or within 24 after completion of surgery. The timing of administration may be e.g. within about 24 hours prior to surgery, such as e.g. within about 12 h, such as e.g. within about 6h, such as e.g. within about 4h, such as e.g. within about 2h, or such as e.g. within about 1 h prior to surgery. In a particular aspect, the administration takes place about 1-2 hours before surgery, or about 2 hours before surgery.

Alternatively, the timing of administration or the one or more antibiotics may be in direct connection with the surgery, i.e. that administration takes place during surgery or immediately after completion of surgery.

In another aspect, the timing of administration of the one or more antibiotics may be within e.g. about 30 min after surgery, or such as e.g. within about 1h after surgery, or such as e.g. within about 2h after surgery, or such as e.g. within about 4h after surgery, or such as e.g. within about 6h after surgery, or such as e.g. within about 12h after surgery, or such as e.g. within about 24h after surgery etc.

As implied above, perioperative administration may also comprise administering one or more antibiotics in any time interval around the point of surgery, such as e.g. within about 24 hours prior to surgery, such as e.g. within about 12 h prior to surgery, such as e.g. within about 6h prior to surgery, such as e.g. within about 4h prior to surgery, such as e.g. within about 2h prior to surgery, or such as e.g. within about 1h prior to surgery, or the one or more antibiotics may be in direct connection with the surgery, i.e. that administration takes place during surgery or immediately after completion of surgery, or the one or more antibiotics may be administered within e.g. about 30 min after surgery, or such as e.g. within about 1h after surgery, or such as e.g. within about 2h after surgery, or such as e.g. within about 4h after surgery, or such as e.g. within about 6h after surgery, or such as e.g. within about 12h after surgery, or such as e.g. within about 24h after surgery, or such as e.g. within about 48h after surgery etc.

In a further aspect, the one or more antibiotics may be administered both prior to, and/or during, and/or post-surgery. For example, the one or more antibiotics may be administered 12h prior to surgery or about 1-2 hours prior to surgery, and/or during the surgery implanting the device or implant, and/or about 1 h after surgery, or such as e.g. within about 2h after surgery, or such as e.g. within about 4h after surgery, or such as e.g. within about 6h after surgery, or such as e.g. within about 12h after surgery, or such as e.g. within about 24h after surgery etc. As mentioned herein, the timing of the administration of the one or more antibiotics is crucial. Waiting with administering the one or more antibiotics after surgery will be less effective or even ineffective. Consequently, waiting with administration of the one or more antibiotics until about 2 days after surgery or longer will be less effective and waiting about 5 days after surgery will largely be ineffective. It is thus crucial to administer the one or more antibiotics so as to enable binding of the one or more antibiotics to the coating material before the surface of the coating material is colonized by bacteria and/or before proteins etc. present in the systemic circulation are able to bind to the surface of the coating material.

As mentioned herein, in one aspect, optionally, the coated implant may additionally be soaked with the one or more antibiotics. This may be employed in combination with administering one or more antibiotics as mentioned above.

In one particular aspect of the invention, the one or more antibiotics may be administered systemically. In one aspect, systemic administration may comprise an injection into the systemic circulation with the one or more antibiotics. Usually, such administration takes place intravenously. Alternatively, the systemic administration may take place orally in form of e.g. a tablet or capsule etc. In another aspect, the administration may be e.g. intraosseous metaphyseal administration. In addition to the perioperative administration mentioned herein, further administrations may take place after the perioperative administration. Consequently, a further dose, or 2 doses, or 3 doses or more may be administered to the subject after the perioperative administration. Expressed in a different way, the subject may receive a first dose 24 h after the perioperative administration and an additional 2^nd dose 48h after the perioperative administration, and yet a further 3^rd dose 72 h after the perioperative administration etc. The inventors of present invention have surprisingly found that the timing of the administration of the one or more antibiotics in relation to the surgery itself influences the effectiveness or any subsequent administration or one or more antibiotics. It has been found that early administration of antibiotics in relation to surgery will entail a better antibiotic effect of any subsequent administration of antibiotics, whereas a later administration will result in a poorer antibiotic effect of any subsequent administration of any antibiotics.

Consequently, present invention relates to use of one or more antibiotics for eliminating, or reducing the risk of bacterial infection in relation to implant surgery, said use comprising: a) administering one or more antibiotics prior to implantation of the implant or device by surgery into the body of the subject, wherein the administration of the one or more antibiotics takes place within 24 h prior to surgery, such as e.g. within about 1-2h prior to surgery, b) implanting the device or implant by surgery into the body of the subject, wherein the device or implant is at least partially coated with a particulate material which may be e.g. hydroxyapatite (HA) or calcium phosphate, wherein one or more antibiotics are administered to the patient during the surgery, c) administering one or more antibiotics to the subject within e.g. about 24 h after completion of implantation surgery.

In a further aspect, present invention relates to a method of eliminating, or reducing the risk of bacterial infection in relation to implant surgery, the method comprising the steps of: a) administering one or more antibiotics prior to implantation of the implant or device into the body of the subject, wherein the administration of the one or more antibiotics takes place within 24 h prior to surgery, such as e.g. within about 1-2h prior to surgery, b) implanting the device or implant into the body of the subject, wherein the device or implant is at least partially coated with a particulate material being hydroxyapatite (HA), wherein one or more antibiotics are administered to the patient during the surgery, c) administering one or more antibiotics to the subject within e.g. about 24 h after completion of implantation surgery.

In one aspect, and wherein the particulate material coated or applied onto the implant or device may be hydroxyapatite, where the hydroxyapatite may be present as the only coating material and consequently without the presence of other materials such as e.g. calcium sulphate etc. In another aspect, the coating particulate material coated or applied onto the implant or device may be calcium phosphate, where the calcium phosphate may be present as the only coating material and consequently without the presence of other materials such as e.g. calcium sulphate etc.

In a further aspect, the material coated or applied onto the implant or device does not comprise calcium sulphate.

As mentioned herein, the at least partially coated device or implant may be pre-treated or soaked with one or more antibiotics prior to the placed inside the body of a subject. This may be done in combination with the perioperative systemic administration of one or more antibiotics. Consequently, and in one non-limiting aspect, dipping the device or implant in the operating theatre with an antibiotic with accretion to the apatite (HA) on e.g. the joint implant surface using a specially formed prosthetic mold in a small container at the same time as the surgeon is preparing for inserting the joint implant may be one manner in pre-treating the the coated implant or device. In one aspect, the antibiotic that may be soaked or otherwise impregnated into the at least partially coated implant or device, may be an antibiotic with a binding affinity towards the material being coated onto the implant or device. In one aspect, the antibiotic may have a high affinity towards HA.

The inventors of present invention has also discovered that when surgery is to be performed in areas of the body where so-called blood emptiness is prevalent, such as e.g. in the knee area, it is particularly advantageous to administer the antibiotic shortly before and during surgery, e.g. in a time span of about 1 h to about 2h before the surgery.

In another aspect, the inventors of present invention have also found that any administration of one or more antibiotics should be administered with 24 hour after completion of surgery. The administration post-surgery may comprise multiple administrations of one or more antibiotics with 24 hours after completion of the surgery.

As is understood from the description, present invention aims at eradicating, reducing or preventing the occurrence of bacterial infection once an implant or device has been placed in the body of a subject. In one aspect, the bacterial infection may be caused by any grampositive or gram-negative bacteria.

In one aspect, the infection may be caused by Staphylococcus aureus, or Staphylococcus epidermidis or any strain thereof.

In a further aspect, the one or more antibiotics used according to the invention, may comprise at least one antibiotic having an affinity towards the coating material applied onto the implant or device. Put differently, at least one of the antibiotics should display an accretion to the coating material. As may be understood from the description, and in such instance two or more antibiotics are being used according to the invention, the additional one or more antibiotics may be the same or different as the antibiotic employed in the first administration. Moreover, and in another aspect, in the case two or more antibiotics are used, one or more may be an antibiotic that does not bind to the apatite or the coating material.

According to present invention, particular patient groups may be particularly suited for the administration regimen disclosed herein. Such patient groups may be but are not limited to e.g. immunocompromised individuals, elderly individuals, individual undergoing treatment against cancer, individuals suffering from obesity, or individuals suffering from diabetes. In the case of patients undergoing treatment for cancer, there is an estimated risk of 15-30% of implant infection. Within the other groups mentioned herein, there is an estimated risk of about 3-5% of implant infection. According to the invention, it is advantageous to delay any medical treatment with a drug that does not have any antibiotic property or activity and which is known to chelate, or otherwise bind to, or have an accretion to calcium. One non-limiting example of such class of drugs may be e.g. bisphosphonates and may consequently be, but not limited to alendronic acid, clodronic acid, etidronic acid, ibandronic acid, neridronic acid, pamidronic acid, risedronic acid, tiludronic acid and zoledronic acid, or any salts thereof.

As mentioned herein, present invention also relates to an implant. The implant may be coated with a particulate material which may in some instances be hydroxyapatite. The particulate material may also be calcium phosphate. The implant which may comprise a coating may also comprise one or more antibiotic compounds. Preferably, the antibiotic compound is a compound which display a high binding affinity to the particulate material. Thus, in one aspect, the antibiotic compound may display a high affinity or binding to hydroxyapatite. In another aspect, the antibiotic compound may display a high binding affinity towards calcium phosphate.

Suitable examples may be e.g. tetracycline, gentamicin, or rifampicin and the likes. In one particular aspect, the antibiotic compound may be tetracycline.

The implant may be an implant suitable for use in e.g. hip replacement and in order to prevent or for use in any bone related tissue.

As is also apparent from the text, the coated device or implant may comprise one or more antibiotic compounds that may be the same or different as the one or more antibiotic compounds that are administered prior to surgery, during surgery or post-surgery.

In one aspect, and based on the diameter of the ZOI (zone of inhibition), it can be interpreted that for the GEN treated implant with a GEN concentration of 40 mg/mL, >10 pg of GEN was released from the implant on day 1.

In a further aspect, and in the case of e.g. RIF treated implant with RIF concentrations of 4 and 40 mg/mL, the RIF released from the implant was > 5 pg on day 1.

Furthermore, for e.g. TET, the implant treated with TET concentrations of 4 and 40 mg/mL, the TET released from the implant was > 30 pg on days 1 and 2.

Thus, according to the invention, the release rate of the antibiotic compound from the implant or device may be in range of at least from about 5 pg to about 50 pg during the first 24 h after implant surgery, such as e.g. about 10 pg to about 30 pg during the first 24 h after implant surgery. The release of the antibiotic compound will continue with similar rates (in the same order of magnitude) during the period of 48 h after implant surgery, or 72 h after implant surgery etc. It is of benefit if the release of the antibiotic compound continues beyond the first 24 h after implant surgery.

EXPERIMENTAL SECTION

The invention is further illustrated in the below non-limiting examples. These are merely one out of several aspects of the invention and should not be construed as limiting of the scope of the invention.

In the below, “HA” means hydroxyapatite. “TET” means tetracycline. “GEN” means gentamicin. “RIF” means rifampicin. “ZOI” means zone of inhibition. “MIC” means minimum inhibitory concentration.

Example 1 : TET interacts with a HA coated implant rapidly and protects it from bacterial colonization.

Methods:

Smith&Nephew HA coated half pin (catalog number 71070819), was machine cut into 4 mm x 4 mm pieces. The cut pieces were then individually placed in a tube containing TET (4 pg/mL, which is the serum concentration of TET in humans). After an incubation time of 1 h, the pieces were removed and washed rigorously with saline three times. After washing, the implants were then placed in a bacterial culture plate containing Staphylococcus aureus (ATCC25923). We then used a Kirby-Bauer disk diffusion test after a 24 h incubation period at 37 °C to evaluate whether bacteria could colonize the implant surface.

As it can be observed from Figure 1 , the implant by itself does not possess any anti-bacterial activity against S. aureus. Once the implant is reacted with a low dose TET in-vitro followed by rigorous washing, which should remove the unbound TET, this experiment could demonstrate that the TET attaches to the surface of the implant and protects the implant from bacterial colonization. This has important clinical implications as HA coated implants could be pretreated in the operating room in a specially formed mold to increase HA-TET binding.

Example 2: HA interaction with serum reduces TET binding affinity

Methods:

Nano and micro-HA powder (100 mg; Fluidnova) was weighed in 2 mL test tubes. Micro-HA power had particles in size range of about 1-10 pm, and nano-HA had a particle size of less than about 50 nm. 1 mL of undiluted Fetal Bovine Serum (FBS) was added to these test tubes in the test group whereas control tubes received 1 mL saline. The HA containing tubes were kept on a rotator at 180 RPM. After 24 h, the tubes were centrifuged at 14000 RPM for 2 min. The supernatant was discarded and sediments were then washed 3 times by adding 1 mL of saline followed by vortex mixing and centrifuging at 14000 RPM for 2 min. After 3 washingcycles, supernatants from the test samples were discarded and 1 mL of TET (4 pg/mL) prepared in undiluted FBS was added to the sediments and mixed. To one set of saline treated control nano-/micro-HA samples, 1 mL of TET (4 pg/mL) prepared in undiluted FBS were added whereas the other set of samples received 1 mL of TET (4 pg/mL) prepared in saline. After 1 and 24 h of mixing, tubes were removed and centrifuged at 14000 RPM for 2 min. The supernatants were discarded and sediments were then washed and their antibacterial effects were tested against a strain of Staphylococcus aureus (ATCC25923) using a Kirby-Bauer disk diffusion test after a 24 h incubation period at 37 °C.

The results of the experiment is illustrated in Figure 2. The protein passivation of the nano/micro-HA particles with FBS significantly affected the ability of TET to chemically interact with HA. Although protein passivation affected the total binding capacity of TET to both type of HA particles, the ZOI of protein passivated HA-TET particles indicates that protein-HA interaction did not completely hinder TET-HA binding and they acquired adequate antibacterial property as well.

Example 3: HA coated metal implants are protected by systemically administered TET

Methods:

Smith&Nephew HA coated half pin (catalog number 71070819), was machine cut into 4 mm x 4 mm pieces. DePuy Synthes titanium K-wire (catalog number 492.100, diameter= 1 mm) was coated with micro particulate HA (size range of about 1-10 m, Captal 30, Plasma Biotal U.K) with a coating thickness of 15-38 pm. Both materials were implanted separately in a burr hole in the proximal tibia of male rats. 4-days (in the case of K-wire) and 7-days (in the case of HA coated pin) post-implantation, animals were administered TET intraperitoneally at a dose of 12.5-25 mg/rat each day for three consecutive days. 24 h after administering the last TET dose, animals were sacrificed and the implanted materials harvested. The harvested material was then dipped in saline solution for 1 min, cleaned with a cotton gauze and placed in a Staphylococcus aureus (ATCC25923). We then used a Kirby-Bauer disk diffusion test after a 24 h incubation period at 37 °C to evaluate whether bacteria could colonize the implant surface.

The results are illustrated in Figure 3. Both types of implants (HA coated half pin and K-wire) coated with HA could be protected from bacterial colonization after TET administration. If TET was not given, it was obvious that the implants were easily infected. Interestingly, when the implant was not coated with HA and TET was repeatedly administered, the implant could not be protected from bacterial colonization either. This experiment therefore clearly demonstrates the importance of HA and the HA seeking property of TET.

Example 4: Early administration of TET protects the implant much better than late TET administration: a clear role of protein passivation.

Methods:

DePuy Synthes titanium K-wire (catalog number 492.100, diameter= 1 mm) was coated with micro particulate HA (size range of about 1-10 m, Captal 30, Plasma Biotal U.K) with a coating thickness of 15-38 pm. The K-wires were implanted in a burr hole in the proximal tibia of male rats. One set of rats received TET peri-operatively i.e. during implantation and in the other set of rats, TET administration started at 5^th day post-surgery. Both sets of animals received either 1 dose (either during surgery and never more than 1 h prior to surgery) or 3 doses of TET (first dose administered either during surgery and never more than 1 h prior to surgery, injected intraperitoneally at a dose of 25 mg/rat) 24 h apart (second and third dose 24 h apart). 24 h after the last dose of TET was administered, the animals were sacrificed and the implanted pins retrieved and subjected to microbiological analysis using the set-up described above.

The results of the experiment are apparent from Figure 5. From the results, two important conclusions can be drawn; 1) Peri-operative TET administration performs better than waiting for 5-days with administering a first dose, since the zone of inhibition is larger when TET is given peri-operatively. 2) Repeated doses of TET (3 in this case) give better results than one single dose, particularly when TET is given peri-operatively rather than postponing a first administration with TET until 5-days after surgery.

These results clearly indicate that the surface of the HA implant is not equally accessible to the circulating TET (i.e. passivated) if TET is administered after a waiting period. This has important implications for prosthetic joint surgery involving implantation of a HA coated implants. In order to protect a HA coated prosthetic joint, TET administration should begin peri- operatively without delays.

The effectiveness of the invention is also demonstrated by comparing the results of Example 3 and 4. If the antibiotic is administered at day 7 or day 5, the ZOI is significantly smaller compared to the peri-operatively administered antibiotic and thus highlighting the absolute importance of the perioperative administration of the antibiotic. Example 5: Antibiotic accretion to hydroxyapatite coating on an implant surface is dependent on the chemical structure and affinity of the antibiotic to hydroxyapatite

Methods:

In this experiment we used a standard ATCC strain (ATCC 25923) of Staphylococcus aureus (S. aureus). A 0.6 mm diameter titanium K-wire (DePuy Synthes, Sweden) was coated with a thin layer of medical grade hydroxyapatite (particle sizes in range of 15 m to 50 pm of which 50% of the particles are about 30 pm, ISO 13779-6 certified) with the coating thickness ranging between 18-35 micrometer. The HA coated K-wire pins were cut into 2-3 mm long pieces using a surgical wire cutter. Care was taken not to chip the HA coating from the implant surface. Three different antibiotics namely gentamycin (GEN), rifampicin (RIF) and tetracycline (TET) were procured from the local pharmacy (Apoteket AB, Sweden) and stock solutions of 40 mg/mL, 4 mg/mL and 0.4 mg/mL were made in normal saline (0.9 wt.%, B Braun). Therefore a total of 9 combinations with the 3 antibiotics and 3 concentrations were obtained.

Two HA (hydroxyapatite) coated pins were immersed in each antibiotic solution containing 0.5 mL of the antibiotic solution at the given concentration. The pins were exposed to the antibiotic solution for 10 min following which they were placed on a sterile cotton gauze and allowed to dry for 1 h. During the drying process, a lawn culture of S. aureus was made on Mueller-Hinton agar plates and at the completion of the drying process at 1 h, the pins from each tube were placed on the agar plates containing the bacteria. The bacterial culture containing the pins was then allowed to be incubated at 37 °C for 24 h before images of the respective zones of inhibition (ZOI) could be captured using a BioRad imager. After the imaging at the end of day 1 , the pins were lifted from the old agar plates and moved to a new plate for repeated incubation for another 24 h. The same process was repeated for each pin until no clear ZOI could be observed for a specific antibiotic coated pin. On first day, each agar plate only contained one HA coated pin per plate. However, depending on the size of the ZOI from the day 1 results, the assay was continued with either one pin per plate of two pins per plate.

Results:

Gentamycin-soaked HA pins had a clear ZOI on day 1 irrespective of the concentration of antibiotic, although the antibiotic concentration affected the total size of the ZOI (as illustrated in Fig. 6).

On day 2, GEN-soaked HA coated pins did not show any ZOI indicating that all of the soak loaded GEN must have left the coating and thereby lost the ability to protect the surface of the implant (as illustrated in Fig. 7). On the contrary, RIF treatment of HA coated implants performed better during the first day after being soaked in the RIF solution (as illustrated in Fig. 8). On day 2, the 40 mg/mL group demonstrated a clear ZOI while the 4 mg/mL group reached < 5 mm (as illustrated in Fig. 9).

As is illustrated in Fig. 9, a measurable ZOI could be observed in the RIF-soaked HA coated pins at medium and high doses on day 2, which diminished entirely by day 3 for 4 mg/mL group and was < 5 mm for the 40 mg/mL group. On day 4, the ZOI for the 40 mg/mL group reached 0.

In the case of TET, a prominent ZOI was observable for all TET concentrations on day 1 (illustrated in Fig. 10), which continued to persist for the 4- and 40 mg/mL groups on day 2.

After day 2, the 40 mg/mL soaked HA pin continued to demonstrate a strong ZOI (15 mm) on day 3 while the bacteria could still not invade the TET soaked pin on day 4 (illustrated in Fig. 11). Finally, on day 5, no ZOI could be observed for the high dose TET sample.

Conclusion:

• Antibiotics GEN (Gentamicin), RIF (Rifampicin) and TET (Tetracycline) all protect an HA coated implant on day 1 and the level of protection is dependent on the concentration of the antibiotic.

• A hydroxyapatite or a calcium phosphate coated implant can be protected from bacterial colonization for different periods of time. The protection time is a direct function of the antibiotics absorption/binding affinity for HA with TET>RIF>GEN in terms of affinity to the coated implant surface.

• We present a method to protect implants from bacterial colonization in an industrially up scalable manner that can provide strong anti-bacterial properties to an implant, provide ease-of-use at point-of-care and reduce problems associated with recalcitrant peri-prosthetic infections.

Claims

1 . An implant or device, wherein the implant or device is at least partially coated with a particulate material and further comprising one or more antibiotic compounds, wherein the particulate material comprises hydroxyapatite or calcium phosphate.

2. The implant or device according to claim 1 , wherein the particulate material has a particle size in range of about 1.0 m to about 50 pm, or about 10 pm, or 10 nm to about 80 nm, or less than about 50 nm, or a mixture of particles of said particle sizes.

3. The implant or device according to claims 1-2, wherein the implant or device comprises a metal or alloy or any suitable ceramic, polymeric material or plastic material.

4. The implant or device according to claims 1-3, wherein the implant or device comprises or consist of a titanium material or titanium alloy, or a cobalt-chromium based alloy or stainless steel.

5. The implant or device according to claims 1-4, wherein the coating has a thickness of about 0.5 pm to about 1000 pm, or about 1 pm to about 500 pm, such as .e.g about 1 pm to about 100 pm, about 1 pm to about 50 pm, about 1 pm to about 25 pm, about 1 pm to about 15 pm, about 1 pm to about 10 pm, or about 1 pm, about 5 pm, about 10 pm, about 15 pm, about 20 pm, about 25 pm, about 30 pm, about 35 pm, about 40 pm, about 45 pm, about 50 pm, about 75 pm, about 100 pm, about 500 pm etc., or the thickness of the coating may be about 1 pm to about 50 pm, or 5 pm to about 50 pm, or about 10 pm to about 45 pm, or about 18 pm to about 35 pm etc.

6. The implant or device according to claims 1-5, wherein the one or more antibiotic compounds have a binding affinity to, or display an accretion to hydroxyapatite or calcium phosphate.

7. The implant or device according to claims 1-6, wherein the one or more antibiotic compounds are selected from tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, tigecycline, omadacycline, sarecyclin or any combinations thereof.

8. The implant or device according to claims 1-7, wherein the one or more antibiotic compounds are selected from ansamycins, such as e.g. rifamycins and in particular rifampicin, geldanamycin, herbimycin A, macbecin, natalamycin, stre ptova ricin or rifamycins in general or any derivatives thereof.

9. The implant or device according to claims 1-8, wherein the one or more antibiotic compounds is rifampicin.

10. The implant or device according to claims 1-9, wherein the antibiotic compound is selected from tetracycline.

11. The implant or device according to claims 1-10, wherein the implant or device is at least partially coated with hydroxyapatite or calcium phosphate of a particle size of about 1 .0 pm to about 50 pm, or about 10 pm, or 10 nm to about 80 nm, or less than about 50 nm, or a mixture of particles of said particle sizes, and wherein the coating has a thickness of about 10 pm to about 45 pm, and wherein the antibiotic compound is tetracyclin and wherein the implant or device is made of titanium or a titanium based alloy.

12. The implant or device according to claims 1-11 , wherein the implant is suitable for use as an implant in relation to bone tissue such as e.g. in the context of hip replacements and the likes.

13. One or more antibiotics for use in preventing, or reducing or treating a bacterial infection in relation to implant surgery, wherein said use comprises a) systemically administering one or more antibiotics to a subject within 24 h prior to surgery, b) performing surgery whereby an implant or device is implanted into the body of a subject, wherein the implant or device is according to any one of claims 1-12, and wherein the one or more antibiotics in the implant or device which may be the same or different from the antibiotics in a) and/or c), c) systemically administering to the subject one or more antibiotics within 24 h post surgery, wherein at least one antibiotic has a binding affinity for, or accretion to hydroxyapatite or calcium phosphate.

14. The one or more antibiotics for use according to claim 13, wherein the one or more antibiotics are also administered to the subject during the surgery and in relation to step b).

15. The one or more antibiotics for use according to claims 13-14, wherein the one or more antibiotics in step a) are administered to the subject within about 1-2 h prior to surgery.

16. The one or more antibiotics for use according to claims 13-15, wherein the one or more antibiotics administered in step c) is administered one or more times within 24 hours after completion of the surgery.

17. The one or more antibiotics for use according to any of the preceding claims 13-16, wherein the hydroxyapatite or calcium phosphate is a finely divided particulate material in a particle size of about 1.0 .m to about 50 .m, or about 10 .m, or 10 nm to about 80 nm, or less than about 50 nm, or a mixture of particles of said particle sizes.

18. The one or more antibiotics for use according to any of the preceding claims 13-17, wherein the antibiotic may be the same or different and selected from tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, tigecycline, omadacycline, sarecyclin or, any ansamycins such as e.g. rifamycins and in particular rifampicin, or geldanamycin, herbimycin A, macbecin, natalamycin, stre ptova ricin or rifamycins in general or a daptomycin, any combinations thereof.

19. The one or more antibiotics for use according to any of the preceding claims 13-18, wherein the coated implant or device is pre-soaked or impregnated with the one or more antibiotics prior to surgery.

20. The one or more antibiotics for use according to any of the preceding claims 13-19, wherein the one or more antibiotics are additionally administered a further 1 time, or 2 times, or 3 times etc. after the administration in step c) and with a 24 hour interval in between administrations.

21 . The one or more antibiotics for use according to any of the preceding claims 13-20, wherein the administration takes place systemically, intravenously or intraosseous by e.g. injection or infusion or orally with any suitable drug formulation, or alternatively by pre-soaking or impregnating of the implant prior to surgery, or any combination thereof.

22. The one or more antibiotics for use according to any of the preceding claims 13-21 , wherein the bacterial infection is caused by e.g. Staphylococcus aureus or Staphylococcus epidermidis, or any other strains thereof.

23. The one or more antibiotics for use according to any of the preceding claims 13-22, wherein the implant or device is not coated with a material comprising calcium sulphate.

24. The one or more antibiotics for use according to any of the preceding claims 13-23, wherein further antibiotics are administered and which do not have a binding affinity towards hydroxyapatite.

25. A method of preparing an implant or device according to any one of the preceding claims 1- 12, the method comprising; a) providing said implant or device further comprising a particulate coating comprising hydroxyapatite or calcium phosphate, b) immersing or soaking or otherwise contacting or depositing onto the implant or device in a) one or more antibiotic compounds, c) with the proviso that one or more antibiotic compounds are present in a solution and the implant or device is soaked into the antibiotic solution, contacting is allowed during a period of time of about 1 minute to about 360 minutes. d) with the proviso that one or more antibiotic compounds are present in a solution, removing the implant or device from the antibiotic solution and allowing the implant or device to dry.

26. The method according to claim 25, wherein subsequently, the device or implant comprising the one or more antibiotic compounds is subjected to any suitable sterilisation procedure.