Background
Methodology
Pathophysiology of septic arthritis : a closer look
New intervention and management approaches
Anti-microbial peptides (AMP’s)
Mechanisms
AMP’s and Septic Arthritis
AMP | Study Highlights | References |
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Engineered chimeric bifunctional peptides (TiBP1-GGG-AMP, and TiBP2-GGG-AMP) | • Two bi-functional chimeric peptides synthesized with an aim to strongly bind to titanium substrate (high affinity) while retaining antimicrobial motif free. • Significant reduction in bacterial adhesion and colonization of S. aureus, S. mutans and E. coli as tested. | [113] |
OP-145 incorporated into Polymer-Lipid Encapsulation Matrix (PLEX)-coating | • Breij and co-workers incorporated a synthetic peptide OP-145 into PLEX coating to obtain high peptide levels for prolonged periods at the implant-tissue interphase. • PLEX coated nails inserted into rabbits inoculated with S. aureus. • Result showed sustained release of OP-145 from plex coatings into the joint space and around the nails. • Effective resolution of induced infection in 67% of test animals within 28 days as shown by culture tests. | [114] |
Five Artificial Peptides synthesized from optimized peptide library | • Bormann and co-researchers synthesized short artificial AMPs using solid phase peptide library. • Later, studied their anti- biofilm potency and their effect on human osteoblast cells. • Peptides showed marked reduction in biofilm formation by S. aureus, E.coli, P. aeruginosa, MRSA and MSSA strains as tested by microcalorimetry and FISH. • Peptides able to significantly reduce internalization of bacteria within osteoblast cells with no effect of viability of human osteoblast cells. | [115] |
Novel in house designed potent ultrashort AMP i.e RBRBR | • Research team developed novel in house designed potent ultrashort AMP i.e RBRBR and encapsulated it in chitosan based nanoparticles using ionotrophic gelation method (RBRBR-CS-NP). • Encapsulated peptide showed progressive sustained release till 14 days. • Signficant decrease in S. aureus counts by three log counts with 98% inhibition of biofilm formation. • No toxicity against mammalian cells and human erythrocytes. | [116] |
LL-37 | • Kang and co-researchers developed 24 hour S. aureus biofilm on cobalt chromium discs followed by treatment with LL-37, AgNP’s and conventional antibiotics combinations. • LL-37 effective in decreasing counts of S. aureus by as high as four log reduction in CFU and this was even more than combination groups i.e AgNP’s and rifampin and even combination of gentamycin and rifampin. • Potential application of LL-37 against bone and joint related biofilm mediated infections strongly advocated. | [117] |
HHC36 peptides | • Chen and co-workers developed a Pandora box approach i.e a novel system promoting on demand release of AMP in and around the affected joint area and implant when bacterial infection occurs and lowers the surrounding pH. • This Pandora box was loaded with HHC36 peptide inside the specially designed titania nanotubes (Ti-NTs) nanotubes and “closed” (surface-modified) with a pH-responsive molecular gate. • The poly (methacrylic acid) (PMAA) swelled under normal conditions (pH 7.4) and collapsed under bacterial infection when pH drops below 6.0 allowing release of AMPs to kill bacteria immediately. • This approach exhibited excellent activity against MRSA, E. coli, P. aeruginosa thus representing a novel smart drug delivery technology worth exploring. | [118] |
Romo1-Derived Antimicrobial Peptide (AMPR-11) | • Lee and team developed AMPR-11, the antimicrobial peptide (AMP) derived from mitochondrial nonselective channel Romo1. • Peptide represents a novel class of fast acting AMP exhibiting broad spectrum antibacterial activity against range of clinical pathogens and multi-drug resistance (MDR) strains. • Exhibits unique mechanism of killing which includes bacterial membranes by interacting with cardiolipin and lipid A. • Exhibited significant activity against intracellular invading bacteria and superior in vivo efficacy in murine model of sepsis. | [119] |
Phage therapy: a new era of treatment
Mechanisms
Phage therapy and SA
Outline of Study | Major Findings | Reference |
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Therapeutic efficacy of cocktail of five phages against S. aureus given intraperitoneally at a dose of 108 PFU/ml in a rat model of joint infection (alone as well as along with vancomycin) | • Phage treatment alone led to 5-fold reduction in bacterial load in the peri-implant tissue. • When given in combination with vancomycin, 6.2 fold reduction occurred. • 22.5 fold decrease in bacterial burden in the joint tissue unlike sham treated animals. • Phage treated animals showed marked reduction in swelling and joint inflammation. | [151] |
• Therapeutic efficacy of MRSA phage MR-5 given single as well as co-therapy with linezolid in resolving MRSA mediated implant infection in mouse model of post arthroplasty joint infection. • Phage MR-5 alone as well as mixed with linezolid was encapsulated in biodegradable HPMC gel and coated onto K-wires. • Coated and uncoated K-wires inserted into the mice femur followed by MRSA inoculation. | • Dual Hydrogel based system exhibited release of both agents i.e phage and linezolid in a slow sustained manner in the joint tissue • Combination therapy showed synergistic effects. • Highest decrease in bacterial burden, improvement in joint mobility and lowered cytokine levels seen in combination group. | [126] |
• To evaluate efficacy of S. aureus specific bacteriophage cocktail formulations against MRSA employing rabbit model of osteomyelitis. • Phage therapy initiated 3-6 weeks post development of experimental osteomyelitis. • Test animals received four repeated doses of seven MRSA phages in a cocktail mix given at the interval of 48 h. | • Test rabbits recovered from the infection within two weeks with marked decline in local oedema, erythema and induration. • Phage treated group showed new bone formation and improved histopathology. | [152] |
• Clinical case study of salvage phage therapy in a 72 year old male with a chronic MRSA prosthetic joint infection. • Infection persisted even after two DAIR procedures. • Patient administered three doses of 2.7 × 109 PFU through i.v route along with daptomycin. | • Phages were able to sterilize the patient’s severe chronic MRSA joint infection with a single virulent bacteriophage given i.v for three days giving negative cultures. | [153] |
Clinical case: • 42-year old man with multidrug-resistant left tibial infection was positive for multidrug resistant strains of Klebsiella pneumoniae and Acinetobacter baumannii. • Patient received combination therapy of bacteriophage (intravenous bacteriophage therapy at 107 PFU/mL titers) and antibiotics. | • Within days of phage administration, the patient showed improved wound healing, decrease in the chronic bone pain. • Negative bacterial cultures obtained for both the causative bacteria and patients’ leg was thus saved from amputation surgery. | [154] |
Adjunctive immunotherapies
Matrix metalloproteinases (MMPs) based therapy
IL-33 receptor (ST2) Deficiency/Blockage as possible Target
IL-15 blockage as possible target
IL-10 Adjunct therapy
IL-4 Blockage as possible Target
Platelet-rich plasma (PRP) based treatment
• Cho et al .[183] developed a novel treatment for end-stage pyogenic arthritis of the hip that consisted of developing antibiotic-loaded cement femoral head spacers. This technique was tested in 10 patients suffering from acute hip arthritis and significant joint destruction. Results demonstrated that the novel femoral head spacer technique showed promising outcomes as seen by decreased pain in the affected hip, better control of the infection with reduced burden of S. aureus and Streptococcus species with preserved proximal femoral bone and soft tissue tension thus overall improving the joint function and mobility in the treated patents. • Hsu et al. [184] developed a novel electrosprayed multi pharmaceutical-loaded Nanoparticle system for direct knee injections for treatment of native septic arthritis. The nanoparticles consisted of lidocaine, vancomycin, ceftazidime–eluting poly (D,L–lactide–co–glycolide) (PLGA). The biodegradable electrosprayed nano/microparticles released high concentrations of antibiotics into the synovial knee tissue of rabbits for more than 2 weeks which was well above the MIC90 for S. aureus. • Schulz et al. [185] reported the use of a novel diagnostic method termed the “Sepsis MetaScore” (SMS) which is an 11-mRNA host immune blood signature. This represents a rapid blood test that can distinguish between bacterial inflammation and non-infectious causes of inflammation thus directing correct treatment to be followed at the earliest. SMS also exhibited a higher degree of sensitivity and accuracy in diagnosing septic joints as compared to other diagnostic biomarkers (ESR, WBC and CRP) that do not help to provide information about bacterial induced or non-bacterial inflammation of the joints. • Similarly, serum Procalcitonin levels (PCT) also represent a sensitive marker for differentiating between septic arthritis and non-septic arthritis [186]. A recent meta-analysis that consisted of 10 studies including 838 patients was aimed to study the usefulness of serum procalcitonin (PCT) as a potential diagnostic marker for correct detection of early septic arthritis (SA) Zhao et al. [187]. Study results indicated and advocated that serum PCT levels represent a sensitive and specific marker with higher diagnostic value than the classical CRP based test and was also to distinguish between SA from non-SA. • Recently, Sultana and Bishayi [188] highlighted the potential use of a drug i.e etoposide that kills the monocyte/macrophage population as a useful adjunct therapy as tested in the mouse model of S. aureus induced SA. Mice were treated with etoposide given subcutaneously post bacterial inoculation. Results showed that the severity of arthritis was lower in the etoposide treated mice as monitored by the overall arthritis index, histopathological picture and decreased levels of pro-inflammatory cytokines, lower levels of reactive oxygen species and reduced levels of MMP-2. |