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.
Highlights
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 c ases[4,5,6]
Pathogens embedded in biofilms have been shown to act as a barrier to the penetration of antibiotics reducing the antibiotic susceptibility compared to their planktonic counterparts[16]
It was hypothesized that the resorbable calcium sulphate phase will provide an initial burst release of both the drugs while RFP or INH could chemically interact with nHAP to provide a sustained release of the drugs over a longer period of time
Summary
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 c ases[4,5,6]. Pathogens embedded in biofilms have been shown to act as a barrier to the penetration of antibiotics reducing the antibiotic susceptibility compared to their planktonic counterparts[16] This leads to persistent or recurrent infections and forcing the clinicians to resort to revision a rthroplasty[17,18]. The aim of this study was to use a biphasic CSH/nHAP based nanocement (NC) carrier for local delivery of two first line ATDs (RFP and INH) to achieve the long-term sustained and controlled release. By achieving this differential release pattern of the added drugs, it might be possible to achieve drug concentrations several times higher than the minimum inhibitory concentration (MIC) or minimum biofilm eradication concentration (MBEC) to initially inhibit the biofilm quorum while the second phase of drug release could potentially eradicate any remaining bacteria in the vicinity
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