Validation of the antibacterial effect of topically applied tranexamic acid using in vitro and in vivo models.

Background: Several studies have shown that tranexamic acid (TXA), an antifibrinolytic, reduces postoperative infection rates. Recent in vitro research showed that TXA alone and in combination with vancomycin and gentamicin had a synergistic effect against some staphylococcal strains. In the present study, this synergistic effect was validated in samples from patients with staphylococcal periprosthetic infection (PPI) and in an in vivo model. Methods: We tested 19 clinical strains (5 Staphylococcus aureus and 14 coagulase-negative staphylococci [CoNS]) against 10 mg/ml TXA alone and in combination with serial dilutions of vancomycin and gentamicin. The standardized microtiter plate method was used. The minimal inhibitory concentration (MIC) were calculated using standard visualization of well turbidity. We also used an S. aureus (ATCC29213) murine subcranial PPI model to compare the synergistic effect of TXA and gentamicin with that of TXA or gentamicin alone after 4 days of monitoring. The mice were euthanized, and disks were removed for analysis of cfu/ml counts and cell viability rate. Biofilm structure of both in vitro and in vivo samples was also analyzed using scanning electron microscopy (SEM). Results: When TXA was combined with vancomycin or gentamicin, the MIC decreased in 30% of the strains studied. According to species, the MIC50 for vancomycin and gentamicin alone and in combination with TXA against S. aureus strains was the same. This was also the case for CoNS with vancomycin and its corresponding combination, whereas with gentamicin and TXA, a reduction in MIC50 was observed (2 dilutions). In addition, in the in vivo model, the mean (SD) log cfu/ml and cell viability rate obtained from the implant was lower in the group of mice treated with TXA and gentamicin than in those treated only with TXA or gentamicin. SEM images also corroborated our findings in strains in which the MIC was reduced, as well as the in the mice implants, with the area occupied by biofilm being greater in samples treated only with gentamicin or TXA than in those treated with TXA+gentamicin. Conclusion: We confirm that combining TXA with vancomycin or gentamicin exerts a synergistic effect. However, this only occurs in selected strains.

Corrigendum: Tranexamic acid in combination with vancomycin or gentamicin has a synergistic effect against staphylococci.

[This corrects the article DOI: 10.3389/fmicb.2022.935646.].

Tranexamic Acid in Combination With Vancomycin or Gentamicin Has a Synergistic Effect Against Staphylococci.

Background: Tranexamic acid (TXA) is an antifibrinolytic agent applied in orthopedic surgery and has been proven to reduce post-surgery infection rates. We previously showed that TXA also had an additional direct antimicrobial effect against planktonic bacteria. Therefore, we aimed to evaluate whether it has a synergistic effect if in combination with antibiotics. Materials and Methods: Three ATCC and seven clinical strains of staphylococci were tested against serial dilutions of vancomycin and gentamicin alone and in combination with TXA at 10 and 50 mg/ml. The standardized microtiter plate method was used. Minimal inhibitory concentrations (MICs) were calculated by standard visualization of well turbidity (the lowest concentration at which complete absence of well bacterial growth was observed by the researcher) and using the automated method (the lowest concentration at which ≥80% reduction in well bacterial growth was measured using a spectrophotometer). Results: Tranexamic acid-10 mg/ml reduced the MIC of vancomycin and gentamicin with both the standard method (V: 1-fold dilution, G: 4-fold dilutions) and the automated turbidity method (vancomycin: 8-fold dilutions, gentamicin: 8-fold dilutions). TXA-50 mg/ml reduced the MIC of gentamicin with both the standard turbidity method (6-fold dilutions) and the automated turbidity method (1-fold dilutions). In contrast, for vancomycin, the MIC remained the same using the standard method, and only a 1-fold dilution was reduced using the automated method. Conclusion: Ours was a proof-of-concept study in which we suggest that TXA may have a synergistic effect when combined with both vancomycin and gentamicin, especially at 10 mg/ml, which is the concentration generally used in clinical practice.

Effect of Tranexamic Acid against Staphylococcus spp. and Cutibacterium acnes Associated with Peri-Implant Infection: Results from an In Vitro Study.

Tranexamic acid (TXA) is extensively used in orthopedic surgery and traumatology as an antifibrinolytic agent to control intra- and postoperative bleeding and, therefore, indirectly, to reduce postsurgery infection rates. The hypothesis of an additional antibiotic effect against microorganisms associated with periprosthetic joint infection needs to be further evaluated. We aimed to assess whether TXA could reduce bacterial growth using an in vitro model. ATCC and clinical strains of staphylococci and Cutibacterium acnes were tested against TXA in both planktonic and sessile forms. We recorded the percent reduction in the following variables: log CFU/mL by microbiological culture, percentage of live cells by confocal laser scanning microscopy, and, additionally in sessile cells, metabolic activity by the 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt (XTT) assay. Variables were compared between groups using the Kruskal-Wallis test, and the results were reported as median (interquartile range [IQR]). Statistical significance was set at a P value of <0.05. Clinical significance was defined as a reduction of ≥25%. TXA at 50 mg/mL led to a slight reduction in CFU counts (4.5%). However, it was at 10 mg/mL that the reduction reached 27.2% and 33.0% for log CFU/mL counts and percentage of live cells, respectively. TXA was not efficacious for reducing preformed 24-h mature staphylococci and 48-h mature C. acnes biofilms, regardless of its concentration. TXA did not exert an antimicrobial effect against bacterial biofilms. However, when bacteria were in the planktonic form, it led to a clinically and statistically significant reduction in bacterial growth at 10 mg/mL. IMPORTANCE The possible use of TXA as an antibiotic agent in addition to its antifibrinolytic effect may play an important role in the prevention of prosthetic joint infection.

Surgical treatment of hip fracture in centenarians: Complications and independent risk factors of death.

BACKGROUND: The increase in life expectancy has led to the appearance of a subgroup of hip fracture (HF) patients with special characteristics known as centenarians. The aim of the present study is to analyse the demographic characteristics, complications and mortality rate of this subgroup in order to identify the specific risk factors for mortality in these patients. METHODS: Retrospective analysis of 69 patients (58 women and 11 men) aged 100 years or older admitted to a tertiary hospital for HF between 1999 and 2018. RESULTS: The average age was 101.3 years (100-108, median 101). More than half (62.3%) of all patients presented with extracapsular fractures. The most common complications observed were delirium (52.3%) and urinary retention (27.7%). Haematoma (9.2%) was the most common surgical complication. Only 3 patients (7.3%) changed their place of residence after admission. In-hospital, 30-day and 1-year mortality rates were 13.8%, 21.5% and 54.2%, respectively. A high Charlson Comorbidity Index and baseline Functional Ambulation Classification (FAC) <3 were associated with a higher in-hospital mortality rate (OR = 1.95 95% CI [1.03-3.69] and OR = 5.7 95% CI [1.2-26.8]), respectively. The presence of more than 3 comorbidities and baseline FAC <3 were associated with a higher risk of 30-day mortality (OR = 6, 95% CI [1.4-24.7] and OR = 4, 95% CI [1.13-14.2]), respectively. Dementia has been associated with a higher risk of 30-day and 1-year mortality (OR = 4.6, 95% CI [1.2-16.7]) and OR = 5.11, 95% CI [1.6-21]) respectively. CONCLUSION: FAC score, number of comorbidities, dementia and the Charlson Comorbidity Index have been shown to be risk factors of mortality in centenarians with HF.

Development of trauma systems in Europe-reports from England, Germany, the Netherlands, and Spain.

Major trauma systems have evolved in many European countries and have resulted in improved care in terms of mortality and morbidity. Many of the systems have similar history, with reports of either poor services, or a single disaster, driving change of policy and set up. We report on 4 European systems, looking at the background, set up and some of the results. Similar issues are identified including the importance of triage, the concentration of specialist skills which require patients to bypass hospitals, and the standardization of treatment protocols. The issues of rehabilitation and the increasing importance of measuring outcome with patient reported metrics are discussed.

A Multicentric, Open-Label, Randomized, Comparative Clinical Trial of Two Different Doses of Expanded hBM-MSCs Plus Biomaterial versus Iliac Crest Autograft, for Bone Healing in Nonunions after Long Bone Fractures: Study Protocol.

ORTHOUNION is a multicentre, open, comparative, three-arm, randomized clinical trial (EudraCT number 2015-000431-32) to compare the efficacy, at one and two years, of autologous human bone marrow-derived expanded mesenchymal stromal cell (hBM-MSC) treatments versus iliac crest autograft (ICA) to enhance bone healing in patients with diaphyseal and/or metaphysodiaphyseal fracture (femur, tibia, and humerus) status of atrophic or oligotrophic nonunion (more than 9 months after the acute fracture, including recalcitrant cases after failed treatments). The primary objective is to determine if the treatment with hBM-MSCs combined with biomaterial is superior to ICA in obtaining bone healing. If confirmed, a secondary objective is set to determine if the dose of 100 × 106 hBM-MSCs is noninferior to that of 200 × 106 hBM-MSCs. The participants (n = 108) will be randomly assigned to either the experimental low dose (n = 36), the experimental high dose (n = 36), or the comparator arm (n = 36) using a central randomization service. The trial will be conducted in 20 clinical centres in Spain, France, Germany, and Italy under the same clinical protocol. The confirmation of superiority for the proposed ATMP in nonunions may foster the future of bone regenerative medicine in this indication. On the contrary, absence of superiority may underline its limitations in clinical use.

An overview of cytokines and heat shock response in polytraumatized patients.

Early after injury, local tissue damage induces a local and systemic inflammatory response that activates the immune system and leads to the development of systemic inflammatory response syndrome (SIRS). This post-traumatic response often results in uncontrolled release of inflammatory mediators and over-activation of the immune system, which occasionally results in multiple organ dysfunction syndrome (MODS). In parallel, a state of immunosuppression develops. This counter-regulating suppression of different cellular and humoral immune functions has been termed "compensatory anti-inflammatory response syndrome (CARS)." Both SIRS and CARS occur simultaneously even in the initial phase after injury. Pro- and anti-inflammatory cytokines have been suggested to play a major role in development of SIRS, although the degree of involvement of the different cytokines is quite disparate. While TNF-α and IL-1ß are quite irrelevant for predicting organ dysfunction, IL-6 is the parameter that best predicts mortality. The hyperinflammatory state seems to be the cause of post-traumatic immunosuppression and heat shock proteins (HSPs), which have been proposed as one of the endogenous stimuli for the deterioration of the immune system acting as danger-associated molecular patterns (DAMPs). Extracellular HSPA1A released from injured tissues increase up to ten times immediately after trauma and even more in patients with MODS. It has powerful immune properties that could contribute to post-traumatic immunosuppression through several mechanisms that have been previously described, so HSPs could represent trauma-associated immunomodulatory mediators. For this reason, HSPA1A has been suggested to be a helpful early prognostic biomarker of trauma after severe injury: serial quantification of serum HSPA1A and anti-Hsp70 concentrations in the first hours after trauma is proposed to be used as a predictive biomarker of MODS and immunosuppression development in polytraumatized patients.

Conversion of arthrodesis to total hip arthroplasty: clinical outcome, complications, and prognostic factors of 21 consecutive cases.

BACKGROUND: Although the results of hip arthrodesis compare favorably with those of total hip arthroplasty (THA) in younger patients, long-term consequences such as osteoarthritis of the neighboring joints may necessitate conversion of the arthrodesis to THA. QUESTIONS/PURPOSES: The purpose of the present study is to assess mid-term clinical outcome and self-perceived improvement in patients who underwent conversion at our department. Secondary aims were incidence of complications and association between patient characteristics and characteristics of the fusions with the outcome of the procedure. PATIENTS AND METHODS: The study sample comprised 21 cases in 20 patients. Minimum follow-up was 3 years (mean, 8 ± 6.5 years) in 20 cases. Thirteen patients had surgical hip fusions and 7 (8 hips) had nonsurgical fusions. Mean age at the time of conversion was 58.5 years. RESULTS: Nineteen out of 21 cases had functioning implants at the latest follow-up visit. According to the Merle d'Aubigné scale, outcome was considered excellent, very good, or good in 15 cases. Lower back pain was reduced in all patients. All but two patients were satisfied after the conversion. The main complications observed included incomplete removal of bone block, intra-operative fractures, dislocation and damage to the femoral artery. Time to conversion and type of fusion had no significant correlation with the clinical outcome. CONCLUSIONS: Conversion THA is a challenging but successful procedure according to the mid-term clinical outcome observed. Our study suggests that, prognostic factors should be used with caution when establishing indications and post-surgical expectations.

Hand-made articulating spacers for infected total knee arthroplasty: a technical note.

The standard treatment for late infections of knee prostheses is a two-stage reimplantation with a temporary articulating spacer between operations, but there is no universal agreement as to the best type of spacer to be used and surgeons have created modifications according to their technical and economic resources. We describe our modified technique for custom-made articulating spacers. Spacers have evolved from simple monoblock designs made of acrylic cement alone to articulated, modular, complex and expensive designs with different grades of constriction. Many surgeons are reluctant to use these devices because of the costs and the potential risks of inserting metallic or plastic elements into a septic joint. Further refinements for customization of articulating spacers have been attempted (Rand 1993, Goldman et al. 1996). We have found no reports describing a technique for making custom hand-made articulating spacers.