A biphasic nanohydroxyapatite/calcium sulphate carrier containing Rifampicin and Isoniazid for local delivery gives sustained and effective antibiotic release and prevents biofilm formation

Abstract

Long term multiple systemic antibiotics form the cornerstone in the treatment of bone and joint tuberculosis, often combined with local surgical eradication. implanted carriers for local drug delivery have recently been introduced to overcome some of the limitations associated with conventional treatment strategies. in this study, we used a calcium sulphate hemihydrate (cSH)/ nanohydroxyapatite (nHAP) based nanocement (NC) biomaterial as a void filler as well as a local delivery carrier of two standard of care tuberculosis drugs, Rifampicin (Rfp) and isoniazid (inH). We observed that the antibiotics showed different release patterns where INH showed a burst release of 67% and 100% release alone and in combination within one week, respectively whereas RFP showed sustained release of 42% and 49% release alone and in combination over a period of 12 weeks, respectively indicating different possible interactions of antibiotics with nHAP. The interactions were studied using computational methodology, which showed that the binding energy of nHAp with Rfp was 148 kcal/mol and INH was 11 kcal/mol, thus varying substantially resulting in RFP being retained in the nHAP matrix. Our findings suggest that a biphasic ceramic based drug delivery system could be a promising treatment alternative to bone and joint tB. Tuberculosis (TB) is a global disease that caused an estimated 1.2 million deaths in 2018 and around 10 million new TB cases were reported globally in the same year, with the incidence being stable in the recent years as per World Health Organization (WHO) report 1 Osteoarticular tuberculosis is a common manifestation accounting for 10-15% of all extrapulmonary TB (EPTB) 2,3 cases and 1-4% of all TB cases 4-6. The bone and joint TB is most often found in spine and weight bearing extremities resulting in neurological complications and joint destruction 7. Treatment modalities include surgical debridement of bone lesions, instrumental stabilisation and filling of dead space with allografts or autograft as well as systemic administration of anti-tuberculosis drugs (ATDs) like Isoniazid (INH), Rifampicin (RFP), Pyrazinamide (PZA), Ethambutol (EMB) and Streptomycin (SM). However, multiple drug resistance and TB recurrence has made it necessary to adhere to long-term, systemic oral use of multiple anti-tuberculosis drugs 8,9. Long-term systemic administration of first line drugs

Bioactive Materials for Soft Tissue Repair

“…Long term multiple systemic antibiotics form the cornerstone in the treatment of bone and joint tuberculosis, often combined with local surgical eradication. These findings suggest that a biphasic ceramic based drug delivery system could be a promising alternative treatment for bone and joint tuberculosis (Qayoom et al, 2020). Indeed, bioceramics carrier systems are employed in the local delivery of growth factors, representing a promising and innovative tool in tissue engineering and dentistry.…”

Local and Sustained Delivery of Rifampicin from a Bioactive Ceramic Carrier Treats Bone Infection in Rat Tibia

“…We have shown that NC could release around 50% of RFP in 12 weeks, thus showing sustained in vitro release unlike isoniazid (INH), which showed burst in vitro release, and around 60% of INH was released within a week. 29 The dissolution of CaS from biphasic NC with time is expected to release the drug and kill the pathogen at the bone nidus. With this dissolution of CaS, the osteoconductive nHAP will serve as a platform for neoosteogenesis by differentiating the infiltrated cells into osteoblasts and hence promote the healing of bone defect created during surgical debridement.…”

“…27 Rifampicin alone has been reported to be more effective against methicillin-resistant Staphylococcus aureus (MRSA) redeemed from device-associated biofilm infections when compared to fusidic acid or ciprofloxacin. 28 Moreover, the interaction of rifampicin with nanohydroxyapatite as shown in our earlier study 29 allows achievement of a long-term sustained release at the infection site. Sustained local delivery of rifampicin will also prevent the emergence of drug-resistant bacteria which often precludes the effectiveness of antibiotics.…”

“…This prevention of emergence of drug-resistant bacteria can be attributed to the regulated and long-term delivery of rifampicin from NC and prevention of biofilm formation on the surface of NC as shown in our previous study. 29 In this study, we aimed to use an indigenously synthesized biphasic calcium sulfate hemihydrate/nanohydroxyapatite (CaS/nHAP) ceramic based nanocement (NC) as a carrier of rifampicin to eradicate the osteomyelitis infection induced by Staphylococcus aureus in rat tibia. Such carriers have also been used in our earlier studies as a carrier of anabolic bone morphogenetic proteins (BMP) or anti-catabolic zoledronate (ZA) molecules to promote fracture healing and bone mineralization in critically sized bone defects and osteoporotic rats, respectively.…”

Nanotechnology-based drug delivery systems in orthopedics

“…Nanotechnology-based antibiotic delivery systems offer many advantages over free antibiotics, including controlled and sustained drug release kinetics, ease of surface modification for bacteria or bone targeting, high local bioactivity, low systemic side effects, ability to deliver multiple antibiotics and, enhanced drug solubility and stability. [54,55] Some nanostructures such as metallic nanoparticles have intrinsic antibacterial activities. Qadri et al [56] utilized antibacterial activity of silvercopper-boron composite nanoparticles to eradicate Staphylococcus aureus bone infection in a mouse osteomyelitis model and demonstrated a potential inorganic route as an antibiotic free and effective alternative approach which could be used for the treatment of osteomyelitis.…”