Local Antibiotic Delivery Options in Prosthetic Joint Infection

Steadman, William; Chapman, Paul R.; Schuetz, Michael; Schmutz, Beat; Trampuž, Andrej; Tetsworth, Kevin

doi:10.3390/antibiotics12040752

Cited by 33 publications

(17 citation statements)

References 157 publications

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“…The elucidation of the translational value of antibiotic-analgesic synergistic use in treating infections holds significant promise for improving patient and overall healthcare outcomes [ 52 ]. The outcomes of PJI are often complicated by virulence, biofilm formation, innate antibiotic resistance, and persistence [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

Sekar,

Gil,

Tierney

et al. 2024

J Transl Med

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Background While antibiotics remain our primary tools against microbial infection, increasing antibiotic resistance (inherent and acquired) is a major detriment to their efficacy. A practical approach to maintaining or reversing the efficacy of antibiotics is the use of other commonly used therapeutics, which show synergistic antibacterial action with antibiotics. Here, we investigated the extent of antibacterial synergy between the antibiotic gentamicin and the anti-inflammatory ketorolac regarding the dynamics of biofilm growth, the rate of acquired resistance, and the possible mechanism of synergy. Methods Control (ATCC 12600, ATCC 35984) and clinical strains (L1101, L1116) of Staphylococcus aureus and Staphylococcus epidermidis with varying antibiotic susceptibility profiles were used in this study to simulate implant-material associated low-risk and high-risk biofilms in vitro. The synergistic action of gentamicin sulfate (GS) and ketorolac tromethamine (KT), against planktonic staphylococcal strains were determined using the fractional inhibitory concentration measurement assay. Nascent (6 h) and established (24 h) biofilms were grown on 316L stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, minimum biofilm eradication concentration (MBEC) measurement for GS, visualization by live/dead imaging, scanning electron microscopy, gene expression of biofilm-associated genes, and bacterial membrane fluidity assessment. Results Gentamicin-ketorolac (GS-KT) combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both ‘low-risk’ and ‘high-risk’ biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin–ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties. Conclusion The results of this study have a significant impact on the local administration of antibiotics and other therapeutic agents commonly used in the prevention and treatment of orthopaedic infections. Further, these results warrant the study of synergy for the concurrent or sequential administration of non-antibiotic drugs for antimicrobial effect.

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Section: Discussionmentioning

confidence: 99%

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

Sekar,

Gil,

Tierney

et al. 2024

J Transl Med

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“…While systemic antibiotics are the main tool in addressing bacterial infections, the implants can be retained or replaced in a one- or two-stage revision [7]. Locally, the elution of aminoglycosides together with vancomycin from antibiotic-eluting bone cement is used to support the role of systemic antibiotics [8]. It is believed that the high concentrations achieved by local administration/elution of drugs will lead to higher efficacy in addressing joint infections while reducing systemic side effects of antibiotics such as nephrotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Investigating the translational value of Periprosthetic Joint Infection (PJI) models to determine the risk and severity of Staphylococcal biofilms

Sekar,

Fan,

Tierney

et al. 2024

Preprint

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With the advent of antibiotic-eluting polymeric materials for targeting recalcitrant infections, using preclinical models to study biofilm is crucial for improving the treatment efficacy in periprosthetic joint infections. The stratification of risk and severity of infections is needed to develop an effective clinical dosing framework with better outcomes. Here, using in-vivo and in-vitro implant-associated infection models, we demonstrate that methicillin-sensitive and resistant Staphylococcus aureus (MSSA and MRSA) have model-dependent distinct implant and peri-implant tissue colonization patterns. The maturity of biofilms and the location (implant vs tissue) were found to influence the antibiotic susceptibility evolution profiles of MSSA and MRSA, and the models were able to capture the differing host-microbe interactions in vivo. Gene expression studies revealed the molecular heterogeneity of colonizing bacterial populations. The comparison and stratification of the risk and severity of infection across different preclinical models provided in this study can aid in guiding clinical dosing to effectively prevent or treat PJI.

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“…Specialized carriers in local DDS offer benefits like improved penetration, sustained release, and localized concentrations, minimizing systemic side effects [ 6 ]. Antibiotics can be delivered with or without a carrier; various carriers include polymethylmethacrylate (PMMA) bone cement, calcium sulfate, calcium hydroxyapatite, bioactive glass, and hydrogels being used [ 7 ]. This approach achieves high local antibiotic concentrations, exceeding the minimum inhibitory concentration (MIC) while reducing systemic levels and associated toxicity, effectively combating biofilms.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Interpretation of Applying Local Drug Delivery System for the Treatment of Deep Surgical Site Infection in the Spine

Madadi,

Sohn

2024

Pharmaceutics

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Surgical site infections (SSIs) after spinal surgery present significant challenges, including poor antibiotic penetration and biofilm formation on implants, leading to frequent treatment failures. Polymethylmethacrylate (PMMA) is widely used for localized drug delivery in bone infections, yet quantifying individual drug release kinetics is often impractical. This retrospective study analyzed 23 cases of deep SSIs (DSSIs) following spinal surgery treated with antibiotic-loaded PMMA. A mathematical model estimated personalized drug release kinetics from PMMA, considering disease types, pathogens, and various antibiotics. The study found that vancomycin (VAN), ceftriaxone (CRO), and ceftazidime (CAZ) reached peak concentrations of 15.43%, 15.42%, and 15.41%, respectively, within the first two days, which was followed by a lag phase (4.91–4.92%) on days 2–3. On days 5–7, concentrations stabilized, with CRO at 3.22% and CAZ/VAN between 3.63% and 3.65%, averaging 75.4 µg/cm2. Key factors influencing release kinetics include solubility, diffusivity, porosity, tortuosity, and bead diameter. Notably, a patient with a low glomerular filtration rate (ASA IV) was successfully treated with a shortened 9-day intravenous VAN regimen, avoiding systemic complications. This study affirms the effectiveness of local drug delivery systems (DDS) in treating DSSIs and underscores the value of mathematical modeling in determining drug release kinetics. Further research is essential to optimize release rates and durations and to mitigate risks of burst release and tissue toxicity.

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Local Antibiotic Delivery Options in Prosthetic Joint Infection

Cited by 33 publications

References 157 publications

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

Investigating the translational value of Periprosthetic Joint Infection (PJI) models to determine the risk and severity of Staphylococcal biofilms

Pharmacokinetic Interpretation of Applying Local Drug Delivery System for the Treatment of Deep Surgical Site Infection in the Spine

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