Pan-genome mediated therapeutic target mining in Kingella kingae and inhibition assessment using traditional Chinese medicinal compounds: an informatics approach.

Kingella kingae causes bacteremia, endocarditis, osteomyelitis, septic arthritis, meningitis, spondylodiscitis, and lower respiratory tract infections in pediatric patients. Usually it demonstrates disease after inflammation of mouth, lips or infections of the upper respiratory tract. To date, therapeutic targets in this bacterium remain unexplored. We have utilized a battery of bioinformatics tools to mine these targets in this study. Core genes were initially inferred from 55 genomes of K. kingae and 39 therapeutic targets were mined using an in-house pipeline. We selected aroG product (KDPG aldolase) involved in chorismate pathway, for inhibition analysis of this bacterium using lead-like metabolites from traditional Chinese medicinal plants. Pharmacophore generation was done using control ZINC36444158 (1,16-bis[(dihydroxyphosphinyl)oxy]hexadecane), followed by molecular docking of top hits from a library of 36,000 compounds. Top prioritized compounds were ZINC95914016, ZINC33833283 and ZINC95914219. ADME profiling and simulation of compound dosing (100 mg tablet) was done to infer compartmental pharmacokinetics in a population of 300 individuals in fasting state. PkCSM based toxicity analysis revealed the compounds ZINC95914016 and ZINC95914219 as safe and with almost similar bioavailability. However, ZINC95914016 takes less time to reach maximum concentration in the plasma and shows several optimal parameters compared to other leads. In light of obtained data, we recommend this compound for further testing and induction in experimental drug design pipeline.Communicated by Ramaswamy H. Sarma.

Right hip gonococcal septic arthritis treatment with successful transition to oral fluoroquinolone.

We present a case of gonococcal septic arthritis of the right hip diagnosed via synovial fluid cultures. Antimicrobial susceptibility testing of the synovial fluid demonstrated susceptibility to tetracycline, ciprofloxacin, cefixime and ceftriaxone. Our patient was initially treated with ceftriaxone and was successfully de-escalated to oral levofloxacin to complete the treatment. This case is interesting given the rarity of disseminated gonococcal infections in the 21st century and that most clinical isolates of Neisseria gonorrhoeae are increasingly resistant to fluoroquinolones.

Calcium sulfate beads made with antibacterial essential oil-water emulsions exhibit growth inhibition against Staphylococcus aureus in agar pour plates.

Calcium sulfate bone void filler beads are fully absorbable in the body, and are often used in complicated orthopedic infection cases to release a relatively high dose of antibiotics locally to the body site over time. However, the antibiotic resistance crisis and/or inability to treat chronic biofilm infections remains to be a formidable and increasing health threat. In this report, we tested the hypothesis that plant essential oils (PEOs) with anti-staphylococcal qualities could inhibit the growth of Staphylococcus aureus (a major etiological agent of periprosthetic joint infection) in agar pour plates when infused in calcium sulfate beads. To begin, we conducted a screen of 57 single plant PEOs for anti-staphylococcal activity via disk diffusions assays. We observed that 55/57 of the PEOs had significant growth inhibitory activity compared to the null hypothesis, and 41/57 PEOs exhibited activity similar-to-or-higher-than a vancomycin minimum inhibitory control. When PEOs were infused in beads, we observed that 17/57 PEOs tested exhibited significant bacterial growth inhibition when encased in S. aureus-seeded agar compared to a null hypothesis of six millimeters (bead size). However, none of the PEO-beads had activity similar to a vancomycin bead control made according to a clinically relevant formula. To the best of our knowledge, this is the first report and screen of PEOs for growth inhibitory activity when infused in lab-made calcium sulfate beads. These data indicate that antibacterial PEOs warrant further investigations, and may be useful in developing new treatment strategies for periprosthetic joint infection.

Adaptive antimicrobial resistance, a description of microbial variants, and their relevance to periprosthetic joint infection.

Periprosthetic joint infection (PJI) is a difficult complication requiring a comprehensive eradication protocol. Cure rates have essentially stalled in the last two decades, using methods of antimicrobial cement joint spacers and parenteral antimicrobial agents. Functional spacers with higher-dose antimicrobial-loaded cement and antimicrobial-loaded calcium sulphate beads have emphasized local antimicrobial delivery on the premise that high-dose local antimicrobial delivery will enhance eradication. However, with increasing antimicrobial pressures, microbiota have responded with adaptive mechanisms beyond traditional antimicrobial resistance genes. In this review we describe adaptive resistance mechanisms that are relevant to the treatment of PJI. Some mechanisms are well known, but others are new. The objective of this review is to inform clinicians of the known adaptive resistance mechanisms of microbes relevant to PJI. We also discuss the implications of these adaptive mechanisms in the future treatment of PJI. Cite this article: Bone Joint J 2022;104-B(5):575-580.

Usefulness of therapeutic drug monitoring in estimating the duration of dalbavancin optimal target attainment in staphylococcal osteoarticular infections: a proof-of-concept.

Dalbavancin is increasingly used for the treatment of staphylococcal osteoarticular infections (OIs). Some population pharmacokinetic studies suggest that a regimen of two 1500 mg doses 1 week apart could ensure effective treatment for several weeks. Here we aim to provide clinicians with a proof-of-concept of the potential role that therapeutic drug monitoring may have in giving real-time feedback of the estimated duration of optimal treatment of staphylococcal OIs with dalbavancin in each single patient.

Clindamycin combination treatment for the treatment of bone and joint infections caused by clindamycin-susceptible, erythromycin-resistant Staphylococcus spp.

The objective of this study was to evaluate the clinical outcomes and safety of clindamycin combination antibiotherapy for the treatment of erythromycin-resistant, lincosamide-susceptible bone and joint infections caused by Staphylococcus spp. Between January 2010 and September 2018, 46 patients with Staphylococcus spp. erythromycin-resistant, lincosamide-susceptible bone and joint infections were treated with clindamycin combination antibiotherapy for 6 to 12 weeks. The type of infection was prosthetic in 20 cases (43.5%), osteosynthetic device in 15 cases (32.6%), chronic osteomyelitis in 7 cases (15.2%), and arthritis in 4 cases (8.7%). The cure rate was 67.4% by intention to treat and 84.6% per protocol, with a median follow-up of 398 days (range 86-843). Only 2 relapses (5.1%) were observed in patients with chronic osteomyelitis; an acquired resistance to lincosamides developed in 1 case. Clindamycin combination therapy appears to be effective for the treatment of bone and joint infection caused by erythromycin-resistant, lincosamide-susceptible Staphylococcus spp.

N-acetylcysteine use as an adjuvant to bone cement to fight periprosthetic joint infections: A preliminary in vitro efficacy and biocompatibility study.

When antibiotic laden bone cement is used to manage periprosthetic joint infection (PJI), failure still occurs with its use in up to 30% of cases. Therefore, we designed an in vitro study to assess the bactericidal effect of N-acetylcysteine (NAC), an antibacterial adjuvant, in cement against planktonic and biofilm forms of common PJI pathogens. NAC (10%, 20%, 30%, 40%, and 50% w/v) added to polymethyl methacrylate (PMMA) and incubated in broth at 36°C. PMMA-alone and/or culture bacteria alone were used as a negative control. Aliquots of cement elution from each group were taken at 1 day and 1 week and then were investigated for antimicrobial efficacy against the planktonic-form and the biofilm-form of Staphylococcus aureus and Escherichia coli. The primary outcome was the residual colony-forming unit count. The cytotoxicity and mechanical properties of the NAC-PMMA cement-blocks were also assessed. NAC-PMMA efficacy against the planktonic bacteria was demonstrated at a minimum of 30% at Day 1 and a minimum of 20% at 1 week after (p < .001). NAC-PMMA cement was effective against biofilm at a minimum of 30% of NAC at 1 day and 1 week of cement immersion (p < .001). The PMMA alone group was identified as having the highest cytotoxicity (p < .001). NAC decreased the stiffness (p = .004) and maximum load breaking point of the cement (p = .029). NAC is an effective and biocompatible adjuvant to PMMA in terms of antibacterial activity against Staphylococcus aureus and Escherichia coli. The broad antibacterial spectrum of NAC, its low expense, and minimal cytotoxicity makes it an ideal agent for addition to PMMA cement.

Medical management of septic arthritis of sternoclavicular joint: A case report.

RATIONALE: Sternoclavicular joint septic arthritis is an unusual disease in healthy adults, and Staphylococcus aureus is the most common causative pathogen. The current treatment of choice is surgery with sternoclavicular joint resection and pectoralis flap closure, especially when the disease is complicated by osteomyelitis and abscess. PATIENT CONCERNS: Here, we report a 76-year-old woman without risk factors who visited our hospital for pain and redness, swelling on the left anterior chest wall. DIAGNOSIS: Magnetic resonance imaging showed infectious arthritis in the left SCJ, with multiple abscess pockets at the subcutaneous layer of anterior chest wall communicating with the joint cavity. Streptococcus agalactiae was isolated from blood culture. INTERVENTION: She was treated with 6 weeks of antibiotic therapy. OUTCOMES: After antibiotic treatment, she was successfully treated without recurrence. LESSONS: Besides surgery, medical treatment should also be considered for sternoclavicular joint septic arthritis, depending on patient status and the causative pathogen. Physicians should be aware of this rare disease to facilitate its prompt diagnosis and management.

Frequency of Dosing of Cephalexin for Oral Step-Down Therapy of Pediatric Osteoarticular Infections Caused by Methicillin-Sensitive Staphylococcus Aureus.

Osteoarticular infections are one of the more common invasive bacterial infections encountered in children. There exist significant practice variations in both the diagnosis and treatment of such infections. However, the practice of transitioning from parenteral therapy to oral antibiotics has been well validated by several studies. For methicillin-sensitive Staphylococcus aureus (MSSA), cephalexin is often recommended. Prospective, controlled data regarding optimal dosing of cephalexin in pediatric osteomyelitis are not available. We sought to review our retrospective, uncontrolled data on four times daily (QID) versus three times daily (TID) dosing of cephalexin for pediatric osteoarticular infections. Children ≥1 month to <18 years of age admitted to Rady Children's Hospital-San Diego with a diagnosis of osteomyelitis or septic arthritis between January 1, 2002, and November 30, 2007, were identified and previously reported. Only patients with culture-positive MSSA infections are included in this report. Demographic and clinical data were manually extracted from the electronic medical record. Fifty-nine patients were treated with cephalexin and had records available for review through our electronic medical record. Thirty-eight patients (64.4%) were treated QID, and 21 patients (35.6%) were treated TID. Clinical cure was achieved in all patients with only one adverse event occurring in the QID group. In this retrospective chart review of children with osteoarticular infections caused by MSSA treated with cephalexin, similar clinical outcomes were found with QID versus TID dosing.

Efficacy evaluation of ethanolic extract of Tamarindus indica L. leaves as possible alternate therapy in septic arthritis model of rabbit.

BACKGROUND: Our previous study exhibited free radicals scavenging and antioxidant activities of ethanolic and aqueous extracts of Tamarindus indica L. leaves in chronic sodium fluoride poisoning in rats. Tamarindus indica L. seed extract was also reported to have anti-arthritic efficacy by inhibiting cartilage and bone degrading factors. Therefore, an attempt was made to evaluate the effects of ethanolic extract of Tamarindus indica L. leaves in septic arthritis. METHODS: The safety study was performed by oral dosing of ethanolic extract of the plant leaves at 2 g kg- 1 for consecutive 28 days in rabbits. Septic arthritis was induced in rabbits by single intra-articular inoculation of 104 c.f.u. of Staphylococcus aureus to the left stifle joint and was monitored by bacterial colony count, some relevant biochemical parameters and histopathological interpretation of the affected joint. For efficacy evaluation in septic arthritis, linezolid at 75 mg kg- 1 twice daily for 10 days and the ethanolic extract of Tamarindus indica L. at 500 and 1000 mg kg- 1 for consecutive 14 days were administered orally to the rabbits after 48 h of induction of arthritis. RESULTS: In sub-acute toxicity study of Tamarindus indica L. leaves ethanolic extract, no significant change between days was found for aspertate aminotransferase, alanine transaminase, alkaline phosphatase, blood urea nitrogen and creatinine compared to day 0 values of the same group. The bacterial colony count of synovial fluid following Staphylococcus aureus inoculation to left stifle joint was found to be 1.08 ± 0.47 and 1.19 ± 0.29 c.f.u. mL- 1 in ethanolic extract low dose and high dose groups respectively, on day 2 which was reduced to 0.057 ± 0.036 c.f.u. mL- 1 and nil on day 16. The test extract was also found to markedly reduce simultaneous glucose difference, total protein ratio of serum and synovial fluid, joint radius and joint narrowing. CONCLUSION: Ethanolic extract of Tamarindus indica L. leaves at 500 mg kg- 1 and 1000 mg kg- 1 produced anti-arthritic effects against S. aureus induced septic arthritis in rabbits. However, the ethanolic extract at 1000 mg kg- 1 orally for consecutive 14 days showed better effects in septic arthritis.

Microbiological profile of septic arthritis in adults: Lessons learnt and treatment strategies.

Objective: The aim of this study is to characterise the clinical and microbiological profile of adult patients treated at our orthopaedic unit with septic arthritic between 2006 and 2017. Materials and Methods: A total of 70 patients who were admitted with a diagnosis of septic arthritis between 2006 and 2017 were included in the study. The patients' clinical and epidemiological characteristics were surveyed; microbiological profile and the complications relating to the patients' treatment were identified. Results: Septic arthritis was more common among males (83%). About 75% of the patients presented with a history of fever. The knee was the most commonly affected joint (71%), followed by the hip. While C-reactive protein was found to be consistently >75, total blood white blood cell (WBC) counts were found not to be reflective of the presence of infection with a mean WBC count of only 13,561/cu.mm, and Gram stain examination had a poor sensitivity of 47%. Among the co-morbidities, the most prevalent association was with diabetes mellitus. The infectious agent most frequently isolated was Staphylococcus aureus(42.85%). The antibiotic sensitivity pattern has evolved since the early years, with resistant strains becoming increasingly prevalent. Unusually, high incidence of streptococci was noted (30%), contrary to the published literature. One-third of the patients had multi-resistant organisms. Septic arthritis left 70% of the patients with a significant residual disability at 6 months follow-up and had 4.25% mortality. Conclusion: Changing sensitivity patterns of microbes in septic arthritis point to a need for reconsidering empirical antibiotic therapy. Joint damage following infection can lead to significant disability.

In Vitro Activity of Rifampin, Rifabutin, Rifapentine, and Rifaximin against Planktonic and Biofilm States of Staphylococci Isolated from Periprosthetic Joint Infection.

The in vitro activities of rifampin, rifabutin, rifapentine, and rifaximin were tested against 200 periprosthetic joint infection (PJI)-associated staphylococci. Seven rifampin-resistant isolates had MICs of ≥4 µg/ml. Three isolates had rifampin MICs of 0.25 to 1 µg/ml and harbored an Asp471Gly RpoB variant, suggesting that the CLSI rifampin-susceptible staphylococcal breakpoint of ≤1 µg/ml may be too high. The remaining isolates had rifampin MICs of ≤0.016 µg/ml, and the rifampin, rifabutin, rifapentine, and rifaximin minimum biofilm bactericidal concentrations (MBBC) for ≥50% of isolates were 8, 1, 2, and 4 µg/ml (for S. aureus) and 2, 0.06, 0.25, and 0.5 µg/ml (for S. epidermidis), respectively, for rifampin-susceptible isolates. Nonrifampin rifamycins have promising staphylococcal activity, including antibiofilm activity.

Amphotericin B Induction with Voriconazole Consolidation as Salvage Therapy for FKS-Associated Echinocandin Resistance in Candida glabrata Septic Arthritis and Osteomyelitis.

We report the case of a 61-year-old female with Crohn's disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of FKS-associated resistance. Infection responded after initiation of amphotericin B plus voriconazole. Echinocandin resistance is increasingly recognized, suggesting a role for alternative antifungal therapies.

Probabilistic chemotherapy in knee and hip replacement infection: the place of linezolid.

Prosthetic joint infection (PJI) can occur with a wide range of microorganisms and clinical features. After replacement surgery of prosthetic joint, prescription of probabilistic broad-spectrum antimicrobial therapy is usual, while awaiting microbial culture results. The aim of our study was to describe the antibiotic susceptibility of microorganisms isolated from hip and knee PJI. The data were collected to determine the best alternative to the usual combination of piperacillin-tazobactam (TZP) or cefotaxime (CTX) and vancomycin (VAN). Based on a French prospective, multicenter study, we analyzed microbiological susceptibility to antibiotics of 183 strains isolated from patients with confirmed hip or knee PJI. In vitro susceptibility was evaluated: TZP+VAN, TZP+linezolid (LZD), CTX+VAN, and CTX+LZD. We also analyzed resistance to different antibiotics commonly used as oral alternatives. Among the 183 patients with PJI, 62 (34%) had a total knee prosthesis, and 121 (66%) a hip prosthesis. The main identified bacteria were Staphylococcus aureus (32.2% of isolates), coagulase-negative staphylococci (27.3%), Enterobacteriaceae (14.2%), and Streptococcus (13.7%). Infections were polymicrobial for 28 (15.3%) patients. All combinations were highly effective: CTX+VAN, CTX+LZD, TZP+VAN, and TZP+LZD (93.4%, 94%, 98.4%, and 98.9% of all cases respectively). Use of LZD instead of VAN in combination with a broad-spectrum beta-lactam covers almost all of the bacteria isolated in PJI. This association should be considered in probabilistic chemotherapy, as it is particularly easy to use (oral administration and no vancomycin monitoring).

Coexisting polyarticular septic arthritis, gout and pseudogout.

A case of a 67-year-old man with coexisting polyarticular septic arthritis due to group G Streptococcus, gout and pseudogout is presented. Septic arthritis of the left knee joint was further complicated by the development of an adjacent osteomyelitis. Appropriate management led to a full clinical recovery. Atypical clinical presentations in elderly, need for a sampling of more than one joint in polyarthritis and a summary of similar cases in literature is discussed.

Una causa inusual de dolor lumbar en paciente con sepsis / An unusual cause of low back pain in a patient with sepsis

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Emergence of a small colony variant of vancomycin-intermediate Staphylococcus aureus in a patient with septic arthritis during long-term treatment with daptomycin.

OBJECTIVES: Small colony variants (SCVs) of Staphylococcus aureus are associated with persistent and drug-resistant infections. We demonstrated for the first time the emergence of SCVs in a patient with vancomycin-intermediate S. aureus (VISA) infection during long-term treatment with daptomycin. METHODS: A 73-year-old man with septic arthritis was infected with VISA. The patient was treated with daptomycin; however, the patient remained infected with VISA, with continuous isolation of VISA from his blood during long-term treatment. Five VISA isolates were characterized by: PFGE; genotyping including staphylococcal cassette chromosome mec (SCCmec), spa and MLST; antimicrobial susceptibility testing; and scanning and transmission electron microscopy. WGS and fatty acid analysis were also performed. RESULTS: The five VISA isolates were from a single clone of ST239/spa3(t037) and, of these, the first three were SCCmecIII positive and daptomycin susceptible, whereas the last two were SCCmecIII negative and daptomycin resistant and exhibited the characteristics of SCVs. The first and last isolates showed 13 remarkable genetic differences in SCCmec and the mprF, cls2, clpX and fabF genes. Of these, mutation of fabF (encoding the fatty acid synthase) seemed to be partially responsible for the slow growth and ultrastructural features, including an abnormal intercellular substance, and for the daptomycin resistance of SCVs. CONCLUSIONS: For the first time, we identified SCVs of VISA in a patient with septic arthritis during long-term treatment with daptomycin. Daptomycin-resistant SCVs of VISA were evolved in a stepwise manner and the mutation of fabF is likely responsible for the physical and ultrastructural characteristics and daptomycin resistance.

Neutrophils and arthritis: Role in disease and pharmacological perspectives.

The inflammatory response in the joint can induce an intense accumulation of leukocytes in the tissue that frequently results in severe local damage and loss of function. Neutrophils are essential cells to combat many pathogens, but their arsenal can contribute or aggravate articular inflammation. Here we summarized some aspects of neutrophil biology, their role in inflammation and indicated how the modulation of neutrophil functions could be useful for the treatment of different forms of arthritis.

Atlanto-axial infection after acupuncture.

A 67-year-old man presented with neck cellulitis following acupuncture for cervical spondylosis. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus. Increased neck pain and bacteraemia prompted MRI, which showed atlanto-axial septic arthritis without signs of infection of the tissues between the superficial cellulitic area and the atlanto-axial joint, thus making direct extension of infection unlikely. It is more likely that haematogenous spread of infection resulted in seeding in the atlanto-axial joint, with the proximity of the arthritis and acupuncture site being coincidental. Acupuncture is a treatment option for some indolent pain conditions. As such, acupuncture services are likely to be more frequently utilised. A history of acupuncture is rarely requested by the admitting doctor and seldom offered voluntarily by the patient, especially where the site of infection due to haematogenous spread is distant from the needling location. Awareness of infectious complications following acupuncture can reduce morbidity through early intervention.

Vertebral Osteomyelitis and Septic Arthritis Associated With Staphylococcus hyicus in a Juvenile Peregrine Falcon ( Falco peregrinus ).

A 6-week-old, parent-reared peregrine falcon ( Falco peregrinus ) was presented with spastic hypertonus of its hind limbs of unknown origin and duration. Radiologic examination revealed smooth periosteal reactions ventrally at thoracic vertebrae 5 to 7. Contrast-enhanced computed tomography identified the swelling as inflammation; antibiotic, antimycotic, anti-inflammatory, and analgesic treatments were initiated, and vitamins and minerals were supplemented. Because the bird's condition did not improve after 10 days, it was euthanatized and submitted for postmortem examination. On histopathologic examination, chronic, active osteomyelitis was diagnosed in thoracic vertebrae 5 to 7, and chronic, active arthritis was present in both the right shoulder and left elbow joints. Staphylococcus hyicus was isolated from these 3 locations, as well as from lungs and liver, indicating a chronic septic staphylococcosis. Although infections with Staphylococcus species are occasional causes of vertebral osteomyelitis in juvenile poultry with active growth plates, it is only sporadically reported in raptors and companion birds. This case report is the first description of the clinical features and diagnostic and pathologic findings in a juvenile peregrine falcon with hematogenous osteomyelitis and arthritis associated with septicemia caused by S hyicus.