BACKGROUND:Total joint arthroplasty (TJA) episodic payment models shift risk and cost of periprosthetic joint infection (PJI) to surgeons and hospitals, causing some to avoid treating high-risk ...patients. Furthermore, there are little data to support optimization of host factors preoperatively to decrease PJI, and recent literature supports using extended antibiotic prophylaxis following reimplantation TJA. The purpose of this study was to evaluate whether extended oral antibiotic prophylaxis minimized PJI after primary TJA in high-risk patients.
METHODS:A retrospective cohort study was performed of 2,181 primary total knee arthroplasties (TKAs) and primary total hip arthroplasties (THAs) carried out from 2011 through 2016 at a suburban academic hospital with modern perioperative and infection-prevention protocols. Beginning in January 2015, extended oral antibiotic prophylaxis for 7 days after discharge was implemented for patients at high risk for PJI. The percentages of patients diagnosed with PJI within 90 days were identified and compared between groups that did and did not receive extended oral antibiotic prophylaxis, with p ≤ 0.05 indicating significance.
RESULTS:The 90-day infection rates were 1.0% and 2.2% after the TKAs and THAs, respectively. High-risk patients without extended antibiotic prophylaxis were 4.9 (p = 0.009) and 4.0 (p = 0.037) times more likely to develop PJI after TKA and THA, respectively, than high-risk patients with extended antibiotic prophylaxis.
CONCLUSIONS:Extended postoperative antibiotic prophylaxis led to a statistically significant and clinically meaningful reduction in the 90-day infection rate of selected patients at high risk for infection. We encourage further study and deliberation prior to adoption of a protocol involving extended oral antibiotic prophylaxis after high-risk TJA, with the benefits weighed appropriately against potential adverse consequences such as increasing the development of antimicrobial resistance.
LEVEL OF EVIDENCE:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Burkholderia pseudomallei is the causative agent of melioidosis, which is endemic primarily in Southeast Asia and northern Australia but is increasingly being seen in other tropical and subtropical ...regions of the world. Melioidosis is associated with high morbidity and mortality rates, which is mediated by the wide range of virulence factors encoded by B. pseudomallei. These virulence determinants include surface polysaccharides such as lipopolysaccharide (LPS) and capsular polysaccharides (CPS). Here, we investigated a predicted arabinose-5-phosphate isomerase (API) similar to KdsD in B. pseudomallei strain K96243. KdsD is required for the production of the highly conserved 3-deoxy-d-manno-octulosonic acid (Kdo), a key sugar in the core region of LPS. Recombinant KdsD was expressed and purified, and API activity was determined. Although a putative API paralogue (KpsF) is also predicted to be encoded, the deletion of
resulted in growth defects, loss of motility, reduced survival in RAW 264.7 murine macrophages, and attenuation in a BALB/c mouse model of melioidosis. Suppressor mutations were observed during a phenotypic screen for motility, revealing single nucleotide polymorphisms or indels located in the poorly understood CPS type IV cluster. Crucially, suppressor mutations did not result in reversion of attenuation
. This study demonstrates the importance of KdsD for B. pseudomallei virulence and highlights further the complex nature of the polysaccharides it produces.
The intrinsic resistance of B. pseudomallei to many antibiotics complicates treatment. This opportunistic pathogen possesses a wide range of virulence factors, resulting in severe and potentially fatal disease. Virulence factors as targets for drug development offer an alternative approach to combat pathogenic bacteria. Prior to initiating early drug discovery approaches, it is important to demonstrate that disruption of the target gene will prevent the development of disease. This study highlights the fact that KdsD is crucial for virulence of B. pseudomallei in an animal model of infection and provides supportive phenotypic characterization that builds a foundation for future therapeutic development.
Abstract Background Despite substantial interest and use of highly cross-linked polyethylene (HXLPE) in total knee arthroplasty (TKA), outcomes remain largely unknown. The purpose of this study is to ...compare HXLPE and conventional polyethylene at 4- to 5-year follow-up. Methods A prospective multicenter study of 307 posterior-stabilized TKAs (168 conventional and 139 HXLPE) was performed. Short-Form-6D, Short-Form 36, Knee Society Score, Lower Extremity Activity Score, health-related quality of life outcomes, and radiographs were collected preoperatively and at routine postoperative intervals. Results Two hundred twenty-four patients obtained a minimum 4- to 5-year follow-up for analysis. There were no osteolysis or polyethylene failures in either group. Although both conventional and HXLPE poly groups showed significant improvements in all measures from preoperative baselines ( P < .05), the XLPE group had slightly greater mean Knee Society Score function ( P = .04), Lower Extremity Activity Score ( P = .03), and Short-Form 36 Physical Composite Score ( P = .03) scores and a greater improvement in Short-Form 6D health-related quality of life of 0.16 points ( d = 1.02, 95% CI: 0.01-1.11) at latest follow-up. Conclusion The study findings support comparative safety and outcomes of HXLPE related to mechanical failure or osteolysis in the midterm. However, longer-term follow-up is warranted to assess whether wear and mechanical properties of HXLPE are maintained in vivo.
The highly virulent intracellular pathogen
is a Gram-negative bacterium that has a wide host range, including humans, and is the causative agent of tularemia. To identify new therapeutic drug targets ...and vaccine candidates and investigate the genetic basis of
virulence in the Fischer 344 rat, we have constructed an
Schu S4 transposon library. This library consists of more than 300,000 unique transposon mutants and represents a transposon insertion for every 6 bp of the genome. A transposon-directed insertion site sequencing (TraDIS) approach was used to identify 453 genes essential for growth
Many of these essential genes were mapped to key metabolic pathways, including glycolysis/gluconeogenesis, peptidoglycan synthesis, fatty acid biosynthesis, and the tricarboxylic acid (TCA) cycle. Additionally, 163 genes were identified as required for fitness during colonization of the Fischer 344 rat spleen. This
selection screen was validated through the generation of marked deletion mutants that were individually assessed within a competitive index study against the wild-type
Schu S4 strain.
The intracellular bacterial pathogen
causes a disease in humans characterized by the rapid onset of nonspecific symptoms such as swollen lymph glands, fever, and headaches.
is one of the most infectious bacteria known and following pulmonary exposure can have a mortality rate exceeding 50% if left untreated. The low infectious dose of this organism and concerns surrounding its potential as a biological weapon have heightened the need for effective and safe therapies. To expand the repertoire of targets for therapeutic development, we initiated a genome-wide analysis. This study has identified genes that are important for
under
and
conditions, providing candidates that can be evaluated for vaccine or antibacterial development.
Liposomal bupivacaine has gained popularity for pain control after total knee arthroplasty (TKA), yet its true efficacy remains unproven. We compared the efficacy of two different periarticular ...injection (PAI) techniques for liposomal bupivacaine with a conventional PAI control group. This retrospective cohort study compared consecutive patients undergoing TKA with a manufacturer-recommended, optimized injection technique for liposomal bupivacaine, a traditional injection technique for liposomal bupivacaine, and a conventional PAI of ropivacaine, morphine, and epinephrine. The optimized technique utilized a smaller gauge needle and more injection sites. Self-reported pain scores, rescue opioids, and side effects were compared. There were 41 patients in the liposomal bupivacaine optimized injection group, 60 in the liposomal bupivacaine traditional injection group, and 184 in the conventional PAI control group. PAI liposomal bupivacaine delivered via manufacturer-recommended technique offered no benefit over PAI ropivacaine, morphine, and epinephrine. Mean pain scores and the proportions reporting no or mild pain, time to first opioid, and amount of opioids consumed were not better with PAI liposomal bupivacaine compared with PAI ropivacaine, morphine, and epinephrine. The use of the manufacturer-recommended technique for PAI of liposomal bupivacaine does not offer benefit over a conventional, less expensive PAI during TKA.
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The post-transcriptional modifier tRNA-(N1G37) methyltransferase (TrmD) has been proposed to be essential for growth in many Gram-negative and Gram-positive pathogens, however ...previously reported inhibitors show only weak antibacterial activity. In this work, optimisation of fragment hits resulted in compounds with low nanomolar TrmD inhibition incorporating features designed to enhance bacterial permeability and covering a range of physicochemical space. The resulting lack of significant antibacterial activity suggests that whilst TrmD is highly ligandable, its essentiality and druggability are called into question.
Abstract Concerns of highly cross-linked polyethylene (XLPE) in total knee arthroplasty (TKA) exist regarding fatigue resistance and oxidation, particularly in posterior-stabilized (PS) designs. A ...prospective cohort study of 114 consecutive PS TKAs utilized conventional polyethylene in 50 knees and second-generation annealed XLPE in 64 TKAs. Clinical (Short-Form 36, Knee Society Scores, and LEAS) and radiographic outcomes were evaluated at a mean of 5 years in 103 TKAs. Mean KSS scores were 12 points higher ( P = 0.01) and SF-36 physical function subset 14 points higher ( P = 0.005) in the XLPE group. There was no radiographic osteolysis or mechanical failure related to the tibial polyethylene in either group. At 5-year follow-up, no deleterious effects related to highly cross-linked posterior stabilized tibial polyethylene inserts were observed.
The intracellular pathogen Burkholderia pseudomallei causes the disease melioidosis, a major source of morbidity and mortality in southeast Asia and northern Australia. The need to develop novel ...antimicrobials is compounded by the absence of a licensed vaccine and the bacterium's resistance to multiple antibiotics. In a number of clinically relevant Gram-negative pathogens, DsbA is the primary disulfide oxidoreductase responsible for catalyzing the formation of disulfide bonds in secreted and membrane-associated proteins. In this study, a putative B. pseudomallei dsbA gene was evaluated functionally and structurally and its contribution to infection assessed.
Biochemical studies confirmed the dsbA gene encodes a protein disulfide oxidoreductase. A dsbA deletion strain of B. pseudomallei was attenuated in both macrophages and a BALB/c mouse model of infection and displayed pleiotropic phenotypes that included defects in both secretion and motility. The 1.9 Å resolution crystal structure of BpsDsbA revealed differences from the classic member of this family Escherichia coli DsbA, in particular within the region surrounding the active site disulfide where EcDsbA engages with its partner protein E. coli DsbB, indicating that the interaction of BpsDsbA with its proposed partner BpsDsbB may be distinct from that of EcDsbA-EcDsbB.
This study has characterized BpsDsbA biochemically and structurally and determined that it is required for virulence of B. pseudomallei.
These data establish a critical role for BpsDsbA in B. pseudomallei infection, which in combination with our structural characterization of BpsDsbA will facilitate the future development of rationally designed inhibitors against this drug-resistant organism.
Trehalose is a disaccharide formed from two glucose molecules. This sugar molecule can be isolated from a range of organisms including bacteria, fungi, plants and invertebrates. Trehalose has a ...variety of functions including a role as an energy storage molecule, a structural component of glycolipids and plays a role in the virulence of some microorganisms. There are many metabolic pathways that control the biosynthesis and degradation of trehalose in different organisms. The enzyme trehalase forms part of a pathway that converts trehalose into glucose. In this study we set out to investigate whether trehalase plays a role in both stress adaptation and virulence of Burkholderia pseudomallei. We show that a trehalase deletion mutant (treA) had increased tolerance to thermal stress and produced less biofilm than the wild type B. pseudomallei K96243 strain. We also show that the ΔtreA mutant has reduced ability to survive in macrophages and that it is attenuated in both Galleria mellonella (wax moth larvae) and a mouse infection model. This is the first report that trehalase is important for bacterial virulence.
The naturally antibiotic-resistant bacterium
is the causative agent of melioidosis, a disease with stubbornly high mortality and a complex, protracted treatment regimen. The worldwide incidence of ...melioidosis is likely grossly underreported, though it is known to be highly endemic in northern Australia and Southeast Asia. Bacterial disulfide bond (DSB) proteins catalyze the oxidative folding and isomerization of disulfide bonds in substrate proteins. In the present study, we demonstrate that
membrane protein disulfide bond protein B (BpsDsbB) forms a functional redox relay with the previously characterized virulence mediator
disulfide bond protein A (BpsDsbA). Genomic analysis of diverse
clinical isolates demonstrated that
is a highly conserved core gene. Critically, we show that DsbB is required for virulence in
A panel of
deletion strains (K96243, 576, MSHR2511, MSHR0305b, and MSHR5858) were phenotypically diverse according to the results of
assays that assess hallmarks of virulence. Irrespective of their
virulence phenotypes, two deletion strains were attenuated in a BALB/c mouse model of infection. A crystal structure of a DsbB-derived peptide complexed with BpsDsbA provides the first molecular characterization of their interaction. This work contributes to our broader understanding of DSB redox biology and will support the design of antimicrobial drugs active against this important family of bacterial virulence targets.
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