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Sonodynamic therapy (SDT) is a promising strategy to treat deep-seated bacterial infections with good tissue penetration and spatiotemporal controllability. However, the low ROS generation efficiency of current sonosensitizers limits the development of SDT. Herein, we report a porphyrin derivative, TAPyPP-2, the sonodynamic activity of which is enhanced with less oxygen dependence by tuning its molecular assembly behavior. TAPyPP-2 can spontaneously form an ultra-small nano-assembly with a diameter of 6 nm in water by conjugation with primary amine salt-decorated pyridinium via π-π staking. The ultra-small assembly behavior can lower the energy gap between singlet and triplet states to 0.01 eV and promote the separation of holes and electrons, which facilitates ROS generation under ultrasound irradiation, in particular type I ROS. The unique hydrophilic ratio and positive charges endow TAPyPP-2 with superior abilities to interact with Staphylococcus aureus , resulting in extremely high sonodynamic antibacterial activity. Therefore, TAPyPP-2 successfully kills Staphylococcus aureus bacteria in the enclosed cavity of synovial joint and achieves effective SDT of septic arthritis. This work is anticipated to motivate enormous interest in the development of efficient SDT.

Rationale: Iliopsoas abscess is a rare acute medical condition. It usually occurs because of the spread of infection from adjacent structures and hematogenous spread. Clinical features include fever, backache, radiating nerve root pain, and leg weakness. When sepsis occurs, prompt recognition is required to initiate appropriate antimicrobial therapy and surgical drainage., Patient Concerns: A 65-year-old male presented to the outpatient department with a 2-day history of lower back, hip, and leg pain, for which analgesics were administered. During hospitalization, he experienced deterioration, becoming febrile, hypoxic, hypotensive, tachycardiac, and delirious., Interventions: The patient was then intubated and ventilated. His family reported an additional history of acupuncture for back pain, which sustained an inflamed wound on his right forearm. Abdominal computed tomography was performed, which confirmed bilateral iliopsoas abscess without involvement of intra-abdominal organs. A preliminary report of blood culture revealed Gram-positive cocci. Echocardiography showed vegetation on the aortic valve, and moderate aortic regurgitation was sustained. He was started on vancomycin along with piperacillin-tazobactam. Ultrasound-guided percutaneous drainage was inserted into the bilateral abscess. Pus and blood yielded methicillin-sensitive Staphylococcus aureus. He remained septic. The repeat computed tomography showed the right abscess enlarged. A repeated echocardiogram showed that the vegetation increased. Further incision and surgical drainage were performed with continuous wash-out., Outcome: His condition improved after management and he was discharged to a regional hospital for ongoing care., Conclusion: Prompt diagnosis and surgical treatment are essential to improve patient outcomes. The unique aspect of this case is the persistence of the methicillin-sensitive Staphylococcus aureus infection. Centralized surgical services are pivotal in conjunction with robust antimicrobial regimens., Lesson: This case reinforces the importance of high clinical suspicion of an unknown source of sepsis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Bovine mastitis is a prevalent infectious disease in dairy herds worldwide, resulting in substantial economic losses. Staphylococcus aureus is a major cause of mastitis in animals, and its antibiotic resistance poses challenges for treatment. Recently, renewed interest has focused on the development of alternative methods to antibiotic therapy, including bacteriophages (phages), for controlling bacterial infections. In this study, 2 lytic phages, vB_SauM_JDYN (JDYN) and vB_SauM_JDF86 (JDF86), were isolated from the cattle sewage effluent samples collected from dairy farms in Shanghai. The 2 phages have a broad bactericidal spectrum against Staphylococcus of various origins. Genomic and morphological analyses revealed that the 2 phages belonged to the Myoviridae family. Moreover, JDYN and JDF86 remained stable under a wide temperature and pH range and were almost unaffected in chloroform. In this study, we prepared a phage cocktail (PHC-1) which consisted of a 1:1:1 ratio of JDYN, JDF86, and SLPW (a previously characterized phage). We found that PHC-1 showed the strongest bacteriolytic effect and the lowest frequency of emergence of bacteriophage insensitive mutants compared with monophages. Bovine mammary epithelial cells and lactating mice mastitis models were used to evaluate the effectiveness of PHC-1 in vitro and in vivo, respectively. The results demonstrated that PHC-1 treatment significantly reduced bacterial load, alleviated inflammatory response, and improved mastitis pathology. Altogether, these results suggest that PHC-1 has the potential to treat S. aureus-induced bovine mastitis and that phage cocktails can combat antibiotic-resistant S. aureus infections., (© 2024, The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Bacterial infections and excessive inflammation present substantial challenges for clinical wound healing. Hydrogels with mild photothermal (PTT) effects have emerged as promising agents owing to their dual actions: positive effects on cells and negative effects on bacteria. Here, an injectable self-healing hydrogel of oxidized konjac glucomannan/arginine-modified chitosan (OKGM/CS-Arg, OC) integrated with protocatechualdehyde-@Fe (PF) nanoparticles capable of effectively absorbing near-infrared radiation is synthesized successfully. The OC/PF hydrogels exhibit excellent mechanical properties, biocompatibility, and antioxidant activity. Moreover, in synergy with PTT, OC/PF demonstrates potent antibacterial effects while concurrently stimulating cell migration and new blood vessel formation. In methicillin-resistant Staphylococcus aureus-infected full-thickness mouse wounds, the OC/PF hydrogel displays remarkable antibacterial and anti-inflammatory activities, and accelerates wound healing by regulating the wound immune microenvironment and promoting M2 macrophage polarization. Consequently, the OC/PF hydrogel represents a novel therapeutic approach for treating multidrug-resistant bacterial infections and offers a technologically advanced solution for managing infectious wounds in clinical settings., (© 2024 Wiley‐VCH GmbH.)

BACKGROUND Facet joint septic arthritis (SAFJ) is a rare clinical entity that is extremely challenging to diagnose, often presenting unilaterally and with nonspecific clinical symptoms. However, SAFJ has significant morbidity and mortality, especially with delayed diagnosis. It becomes all the more important for the clinician to recognize that SAFJ can present bilaterally and be associated with direct inoculation, such as in acupuncture. CASE REPORT A 53-year-old woman with chronic alcoholism and well-controlled type 2 diabetes mellitus was initially admitted for progressively worsening atraumatic lower back pain. Initial non-contrast magnetic resonance imaging (MRI) of the lumbar spine revealed bilateral L4-L5 and L5-S1 nonspecific facet joint effusions. Clinical examination was unremarkable. Biochemically, the patient had mildly elevated inflammatory markers. She was treated conservatively with close outpatient follow-up. However, her back pain progressively worsened, with new-onset lower limb weakness and numbness. Repeat MRI showed L4-L5 bilateral facet joint fluid collection with adjacent bony destruction, as well as posterior paraspinal and epidural fluid collections compatible with L4-L5 bilateral SAFJ with paraspinal and epidural abscesses. Urgent surgical drainage and bilateral lateral facet decompression was performed. Intraoperative cultures revealed methicillin-sensitive Staphylococcus aureus as the causative organism. Postoperatively, 6 weeks of intravenous and oral antibiotics were given with good recovery. CONCLUSIONS We describe a case of bilateral SAFJ following acupuncture that was initially missed. With the increasing prevalence of acupuncture treatment for lower back pain, bilateral SAFJ should be a diagnostic consideration. Detailed clinical history is key; this, as well as a high index of suspicion, early evaluation and treatment, are essential to obtain a favorable outcome.

Skin and soft tissue infections (SSTIs) represent a significant healthcare challenge, particularly in the context of increasing antibiotic resistance. This study investigates the efficacy of a novel therapeutic approach combining bacteriophage (phage) therapy with a gum Karaya (GK)-based hydrogel delivery system in a porcine model of deep staphylococcal SSTIs. The study exploits the lytic activity and safety of the Staphylococcus phage 812K1/420 of the Kayvirus genus, which is active against methicillin-resistant Staphylococcus aureus (MRSA). The GK injectable hydrogels and hydrogel films, developed by our research group, serve as effective, non-toxic, and easy-to-apply delivery systems, supporting moist wound healing and re-epithelialization. In the porcine model, the combined treatment showed asynergistic effect, leading to a significant reduction in bacterial load (2.5 log CFU/gram of tissue) within one week. Local signs of inflammation were significantly reduced by day 8, with clear evidence of re-epithelialization and wound contraction. Importantly, no adverse effects of the GK-based delivery system were observed throughout the study. The results highlight the potential of this innovative therapeutic approach to effectively treat deep staphylococcal SSTIs, providing a promising avenue for further research and clinical application in the field of infections caused by antibiotic-resistant bacteria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Staphylococcus aureus is a pathogenic bacterium responsible for a broad spectrum of infections, including cutaneous, respiratory, osteoarticular, and systemic infections. It poses a significant clinical challenge due to its ability to develop antibiotic resistance. This resistance limits therapeutic options, increases the risk of severe complications, and underscores the urgent need for new strategies to address this threat, including the investigation of treatments complementary to antibiotics. The evaluation of novel antimicrobial agents often employs animal models, with the zebrafish embryo model being particularly interesting for studying host-pathogen interactions, establishing itself as a crucial tool in this field. For the first time, this study presents a zebrafish embryo model for the in vivo assessment of bacteriophage efficacy against S. aureus infection. A localized infection was induced by microinjecting either methicillin-resistant S. aureus (MRSA) or methicillin-susceptible S. aureus (MSSA). Subsequent treatments involved administering either bacteriophage, vancomycin (the reference antibiotic for MRSA), or a combination of both via the same route to explore potential synergistic effects. Our findings indicate that the bacteriophage was as effective as vancomycin in enhancing survival rates, whether used alone or in combination. Moreover, bacteriophage treatment appears to be even more effective in reducing the bacterial load in S. aureus -infected embryos post-treatment than the antibiotic. Our study validates the use of the zebrafish embryo model and highlights its potential as a valuable tool in assessing bacteriophage efficacy treatments in vivo ., Competing Interests: The authors declare no conflict of interest.

Bacterial infections pose a global concern due to high fatality rates, particularly with the rise of drug-resistant bacteria and biofilm formation. There is an urgent need for innovative strategies to combat this issue. A study on chemodynamic therapy (CDT) using nanozymes in conjunction with photothermal therapy (PTT) has displayed potential in addressing drug-resistant bacterial infections. However, the effectiveness of this combined approach is limited by inadequate light absorption. This work suggests the NiOx nanoparticles enriched with oxygen vacancies enhance CDT and PTT to overcome this challenge. The presence of oxygen vacancies in NiOx can reduce the energy gap between its valence band and conduction band, facilitating oxygen adsorption. NiOx has exhibited notable antibacterial properties and complete eradication of biofilms in both laboratory and animal trials. In animal abscess models, NiOx demonstrated antibacterial and anti-inflammatory effects in the initial stages, while also promoting wound healing and tissue regeneration by influencing immune factors and encouraging collagen deposition and neovascularization. With positive biosafety and biocompatibility profiles, the oxygen vacancy-enhanced CDT and PTT therapy proposed in this article hold promise for effective sterilization, deep biofilm removal, and treatment of infections caused by drug-resistant bacteria. STATEMENT OF SIGNIFICANCE: This study constructs oxygen vacancies NiOx nanoparticles (NiOx NPs) to improve the efficacy of photothermal therapy and chemodynamic therapy. The presence of oxygen vacancies in NiOx NPs helps bridge the energy gap between its valence band and conduction band, facilitating oxygen adsorption and improving catalytic efficiency. In both in vivo and in vitro antibacterial experiments, NiOx NPs demonstrate effective antibacterial and anti-inflammatory properties. Furthermore, it aids in wound healing and tissue regeneration by modulating immune factors, collagen deposition, and angiogenesis. This approach presents a promising collaborative strategy for utilizing nickel-based defective nanomaterials in combating deep drug-resistant bacterial infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Due to the advanced studies on stem cells in developmental biology, the roles of stem cells in the body and their phenotypes in related diseases have not been covered clearly. Meanwhile, with the intensive research on the mechanisms of stem cells in regulating various diseases, stem cell therapy is increasingly being attention because of its effectiveness and safety. As one of the most widely used stem cell in stem cell therapies, hematopoietic stem cell transplantation shows huge advantage in treatment of leukemia and other blood-malignant diseases. Besides, due to the effect of anti-inflammatory and immunomodulatory, mesenchymal stem cells could be a potential therapeutic strategy for variety infectious diseases. In this review, we summarized the effects of Staphylococcus aureus (S. aureus) and its components on different types of adult stem cells and their downstream signaling pathways. Also, we reviewed the roles of different kinds of stem cells in various disease models caused by S. aureus, providing new insights for applying stem cell therapy to treat infectious diseases., (© 2024. The Author(s).)

Metal-implant associated bacterial infections are a major clinical problem due to antibiotic treatment failure. As an alternative, we determined the effects of bacteriophage ISP on clinical isolates of Staphylococcus aureus in various stages of its life cycle in relation to biofilm formation and maturation. ISP effectively eliminated all planktonic phase bacteria, whereas its efficacy was reduced against bacteria attached to the metal implant and bacteria embedded within biofilms. The biofilm architecture hampered the bactericidal effects of ISP, as mechanical disruption of biofilms improved the efficacy of ISP against the bacteria. Phages penetrated the biofilm and interacted with the bacteria throughout the biofilm. However, most of the biofilm-embedded bacteria were phage-tolerant. In agreement, bacteria dispersed from mature biofilms of all clinical isolates, except for LUH15394, tolerated the lytic activity of ISP. Lastly, persisters within mature biofilms tolerated ISP and proliferated in its presence. Based on these findings, we conclude that ISP eliminates planktonic phase Staphylococcus aureus while its efficacy is limited against bacteria attached to the metal implant, embedded within (persister-enriched) biofilms, and dispersed from biofilms., (© 2024. The Author(s).)

We present a case of deep surgical site infection (SSI) at a spinal cord stimulator (SCS) trial implantation site, resulting from an allergic reaction to an unknown agent. A 38-year-old female with complex regional pain syndrome began an SCS trial, noting 100% pain relief for 5 days. Fluid drainage from the surgical site was reported on POD6 and trial leads were removed the following day. The patient was hospitalized with sepsis. Blood cultures revealed Staphylococcus aureus . MRIs showed skin breakdown and cellulitis of the paraspinal musculature extending into the epidural space. The patient was maintained with antibiotics and rigorous wound care for 9 days and the surgical site infection resolved. The patient proceeded to SCS implantation, and reported good pain relief with the implanted device.

Bacterial infections trigger inflammation and impede the closure of skin wounds. The misuse of antibiotics exacerbates skin infections by generating multidrug-resistant bacteria. In this study, we developed chemo-photothermal therapy (chemo-PTT) based on near-infrared (NIR)-irradiated chitosan/gold nanorod (GNR) clusters as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents. The nanocomposites exhibited an average size of 223 nm with a surface charge of 36 mV. These plasmonic nanocomposites demonstrated on-demand and rapid hyperthermal action under NIR. The combined effect of positive charge and PTT by NIR-irradiated nanocomposites resulted in a remarkable inhibition rate of 96 % against planktonic MRSA, indicating a synergistic activity compared to chitosan nanoparticles or GNR alone. The nanocomposites easily penetrated the biofilm matrix. The combination of chemical and photothermal treatments by NIR-stimulated clusters significantly damaged the biofilm structure, eradicating MRSA inside the biomass. NIR-irradiated chitosan/GNR clusters increased the skin temperature of mice by 13 °C. The plasmonic nanocomposites induced negligible skin irritation in vivo. In summary, this novel nanosystem demonstrated potent antibacterial effects against planktonic and biofilm MRSA, showcasing the possible efficacy in treating skin infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) emphasises the urgent need for novel antimicrobial agents as alternatives to antibiotics. Bacteriophage therapy is one of the most promising antimicrobial strategies. Here, we isolated and comprehensively characterized a novel Staphylococcus phage, vB_SauM_VL10 (VL10), from urban sewage. The VL10 genome displays 141,746 bp of linear double-stranded DNA, containing 193 open reading frames and lacking tRNA, virulence, or antibiotic resistance genes. Phylogenetic analysis categorizes VL10 as a novel species within the Silviavirus genus, Twortvirinae subfamily. VL10 exhibits lytic behaviour characterized by efficient adsorption, a short latent period, and substantial burst size, with environmental stability. It demonstrates lytic activity against 79.06% of tested S. aureus strains, highlighting its species specificity. Additionally, VL10 effectively targets MRSA biofilms, reducing biomass and viable cells. In MRSA-infected G. mellonella larvae, VL10 enhances survival rates, supporting its potential for phage therapy applications. Moreover, the emergence of VL10-resistant S. aureus strains associated with fitness trade-offs, including reduced growth, biofilm formation, and virulence. Altogether, these findings emphasize VL10 as a promising candidate for developing therapeutic agents against MRSA infections, providing insights into phage biology and resistance dynamics., (© 2024. The Author(s).)

Osteomyelitis caused by deep tissue infections is difficult to cure through phototherapy due to the poor penetration depth of the light. Herein, Cu/C/Fe 3 O 4 -COOH nanorod composites (Cu/C/Fe 3 O 4 -COOH) with nanoscale tip convex structures are successfully fabricated as a microwave-responsive smart bacteria-capture-killing vector. Cu/C/Fe 3 O 4 -COOH exhibited excellent magnetic targeting and bacteria-capturing ability due to its magnetism and high selectivity affinity to the amino groups on the surface of Staphylococcus aureus (S. aureus). Under microwave irradiation, Cu/C/Fe 3 O 4 -COOH efficiently treated S. aureus-infected osteomyelitis through the synergistic effects of microwave thermal therapy, microwave dynamic therapy, and copper ion therapy. It is calculated the electric field intensity in various regions of Cu/C/Fe 3 O 4 -COOH under microwave irradiation, demonstrating that it obtained the highest electric field intensity on the surface of copper nanoparticles of Cu/C/Fe 3 O 4 -COOH due to its high-curvature tips and metallic properties. This led to copper nanoparticles attracted more charged particles compared with other areas in Cu/C/Fe 3 O 4 -COOH. These charges are easier to escape from the high curvature surface of Cu/C/Fe 3 O 4 -COOH, and captured by adsorbed oxygen, resulting in the generation of reactive oxygen species. The Cu/C/Fe 3 O 4 -COOH designed in this study is expected to provide insight into the treatment of deep tissue infections under the irradiation of microwave., (© 2023 Wiley‐VCH GmbH.)

Objective: Staphylococcus aureus fracture-related infections (FRIs) are associated with significant morbidity in part because conventional antibiotic therapies have limited ability to eradicate S. aureus in sessile states. Therefore, the objective of this study was to assess the feasibility of using Staphylococcal bacteriophages for FRI by testing the activity of a library of Staphylococcal bacteriophage therapeutics against historically preserved S. aureus FRI clinical isolates., Methods: Current Procedural Terminology codes were used to identify patients with FRI from January 1, 2021 to December 31, 2021. Preserved S. aureus FRI isolates from the cases were then tested against a library of 51 Staphylococcal bacteriophages from an American company. This was conducted by assessing the ability of bacteriophages to reduce bacterial growth over time. Growth inhibition greater than 16 h was considered adequate for this study., Results: All of the S. aureus preserved clinical isolates had at least one bacteriophage with robust lytic activity and six bacteriophages (11.8 %) had robust lytic activity to seven or more of the clinical isolates. However, 41 of the bacteriophages (80.4 %) had activity to less than three of the clinical isolates and no bacteriophage had activity to all the clinical isolates., Conclusion: Our findings show that Staphylococcal bacteriophage therapeutics are readily available for S. aureus FRI clinical isolates. However, when correlated with the current barriers to using bacteriophages to treat FRI, designated Staphylococcal bacteriophage cocktails with broad spectrum activity should be created., Competing Interests: Declaration of competing interest J. B. Doub was a previous consultant with Adaptive Phage Therapeutics and currently is receiving a grant (13582210) from the National Institutes of Health. J. Fackler is an employee of Adaptive Phage Therapeutics. R. V. O'Toole is a paid consultant for Stryker, receives stock options from Imagen, and receives royalties from Lincotek, all unrelated to this research. The remaining authors report no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Staphylococcus epidermidis is a common member of the human skin and nose microbiomes and a frequent cause of invasive infections. Transducing phages accomplish the horizontal transfer of resistance and virulence genes by mispackaging of mobile-genetic elements, contributing to severe, therapy-refractory S. epidermidis infections. Lytic phages on the other hand can be interesting candidates for new anti-S. epidermidis phage therapies. Despite the importance of phages, we are only beginning to unravel S. epidermidis phage interactions. Recent studies shed new light on S. epidermidis phage diversity, host range, and receptor specificities. Modulation of cell wall teichoic acids, the major phage receptor structures, along with other phage defense mechanisms, are crucial determinants for S. epidermidis susceptibility to different phage groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Staphylococcus aureus is one of the most common infectious agents, causing morbidity and mortality worldwide. Most pathogenic bacteria are classified in the group of mesophilic bacteria and the optimal growth temperature of these bacteria changes between 33 and 41 °C. Increased temperature can inhibit bacterial growth and mobility, which in turn, can trigger autolysis and cause cell wall damage. Hyperthermia treatment is defined as a heat-mediated treatment method applied using temperatures higher than body temperature. Nowadays, this treatment method is used especially in the treatment of tumours. Hyperthermia treatment is divided into two groups: mild hyperthermia and ablative or high-temperature hyperthermia. Mild hyperthermia is a therapeutic technique in which tumour tissue is heated above body temperature to produce a physiological or biological effect but is often not aimed at directly causing significant cell death. The goal of this method is to achieve temperatures of 40-45 °C in human tissues for up to 2 h. Hyperthermia can be used in the treatment of infections caused by such bacterial pathogens. In addition, using hyperthermia in combination with antimicrobial drugs may result in synergistic effects and reduce resistance issues. In our study, we used two different temperature levels (37 °C and 45 °C). We assessed growth inhibition, some virulence factors, alteration colony morphologies, and antimicrobial susceptibility for several antibiotics with three methods (Kirby-Bauer, E-test and broth microdilution) under hyperthermia. In the study, we observed that hyperthermia affected the urease enzyme, antibiotic sensitivity levels showed synergy with hyperthermia, and changes occurred in colony diameters and affected bacterial growth. We hypothesise that hyperthermia might be a new therapeutic option for infectious diseases as a sole agent or in combination with different antimicrobials., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Personalized clinical management of spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) is challenging due to limited evidence of microbiologic findings and their clinical impact during the clinical course of the disease. We aimed to characterize clinico-microbiological and imaging phenotypes of SD and ISEE to provide useful insights that could improve outcomes and potentially modify guidelines., Methods: We performed chart review and collected data on the following parameters: bacterial antibiogram-resistogram, type of primary spinal infection, location of spinal infection, source of infection, method of detection, clinical complications (sepsis, septic embolism, and endocarditis), length of hospital and intensive care unit (ICU) stay, relapse rate, and disease-related mortality in patients with proven pyogenic SD and ISEE treated surgically in a university hospital in Germany between 2002 and 2022., Results: We included data from 187 patients (125 SD, 66.8% and 62 ISEE, 33.2%). Gram-positive bacteria (GPB) were overall more frequently detected than gram-negative bacteria (GNB) (GPB: 162, 86.6% vs. GNB: 25, 13.4%, p < 0.001). Infective endocarditis was caused only by GPB (GPB: 23, 16.5% vs. GNB: 0, 0.0%, p = 0.046). Methicillin-susceptible Staphylococcus aureus was the most frequently isolated strain (MSSA: n = 100, 53.5%), occurred more frequently in the cervical spine compared to other bacteria (OB) (MSSA: 41, 41.0% vs. OB: 18, 20.7%, p = 0.004) and was most frequently detected in patients with skin infection as the primary source of infection (MSSA: 26, 40.6% vs. OB: 11, 16.7%, p = 0.002). Streptococcus spp. and Enterococcus spp. (SE: n = 31, 16.6%) were more often regarded as the cause of endocarditis (SE: 8, 27.6% vs. OB: 15, 11.4%, p = 0.037) and were less frequently detected in intraoperative specimens (SE: 19, 61.3% vs. OB: 138, 88.5%, p < 0.001). Enterobacterales (E: n = 20, 10.7%) were identified more frequently in urinary tract infections (E: 9, 50.0% vs. OB: 4, 3.6%, p < 0.001). Coagulase-negative Staphylococci (CoNS: n = 20, 10.7%) were characterized by a lower prevalence of sepsis (CoNS: 4, 20.0% vs. OB: 90, 53.9%, p = 0.004) and were more frequently detected in intraoperative specimens (CoNS: 20, 100. 0% vs. OB: 137, 82.0%, p = 0.048). Moreover, CoNS-associated cases showed a shorter length of ICU stay (CoNS: 2 [1-18] days vs. OB: 6 [1-53] days, median [interquartile range], p = 0.037), and occurred more frequently due to foreign body-associated infections (CoNS: 8, 61.5% vs. OB: 15, 12.8%, p = 0.008). The presence of methicillin-resistant Staphylococcus aureus (MRSA) prolonged hospital stay by 56 [24-58] days and ICU stay by 16 [1-44] days, whereas patients with Pseudomonas aeruginosa spent only 20 [18-29] days in the hospital and no day in the ICU 0 [0-5] days., Conclusions: Our retrospective cohort study identified distinct bacterial-specific manifestations in pyogenic SD and ISEE regarding clinical course, neuroanatomic targets, method of pathogen detection, and sources of infection. The clinico-microbiological patterns varied depending on the specific pathogens., (© 2023. The Author(s).)

Introduction: Infections related to deep brain stimulation (DBS) can lead to discontinuation of the treatment and increased morbidity. Various measures of reducing infection rates have been proposed in the literature, but scientific consensus is lacking. The aim of this study was to report a 26-year single center experience of DBS infections and provide recommendations for the prevention and management of them., Methods: The retrospective analysis consisted of 978 DBS surgeries performed at Oulu University Hospital (OUH) from 1997 to 2022. This included 342 primary or reimplantations of DBS electrodes and 559 primary or reimplantations of implantable pulse generator (IPG). Infections within approximately 1 year after the surgery without secondary cause were considered surgical-site infections (SSIs). χ2 test was used to compare infection rates before and after 2013, when the systematic implementation of infection prevention measures was started., Results: A total of 35 DBS implants were found to be infected. The number of SSIs was 30, of which 29 were originally operated in OUH leading to a center-specific infection rate of 3.1%. Of the SSIs, 17.2% occurred after IPG replacement. Staphylococcus aureus was found in 75.0% of cultures and 32.1% were mixed infections. The treatment of SSIs included aggressive surgical revision combined with cefuroxime and vancomycin antibiotics, as most patients in the initial conservative treatment group eventually required surgical revision. A statistically significant difference in infection rates before and after the implementation of preventative measures was not observed (risk ratio 2.20, 95% confidence interval 0.94-5.75, p = 0.051), despite over two-fold difference in the incidence of SSIs., Conclusion: Our findings show that the rates of surgical infections are low in modern DBS, but due to their serious consequences, preventative measures should be implemented. We highlight that mixed infections should be accounted for in the antibiotic selection. Furthermore, our treatment recommendation includes aggressive surgical revision combined with antibiotic treatment., (© 2024 S. Karger AG, Basel.)

Staphylococcus sp. is the most common bacterial genus in infections related to diabetic foot ulcers (DFUs). The emergence of multidrug-resistant bacteria places a serious burden on public health systems. Phage therapy is an alternative treatment to antibiotics, overcoming the issue of antibiotic resistance. In this study, six phages (SAVM01 to SAVM06) were isolated from effluents and were used against a panel of staphylococcal clinical samples isolated from DFUs. A genomic analysis revealed that the phages belonged to the Herelleviridae family, with sequences similar to those of the Kayvirus genus. No lysogeny-associated genes, known virulence or drug resistance genes were identified in the phage genomes. The phages displayed a strong lytic and antibiofilm activity against DFU clinical isolates, as well as against opportunistic pathogenic coagulase-negative staphylococci. The results presented here suggest that these phages could be effective biocontrol agents against staphylococcal clinical isolates from DFUs.

S. aureus is a pathogen that frequently causes severe morbidity and phage therapy is being discussed as an alternative to antibiotics for the treatment of S. aureus infections. In this in vitro and animal study, we demonstrated that the activity of anti-staphylococcal phages is severely impaired in 0.5% plasma or synovial fluid. Despite phage replication in these matrices, lysis of the bacteria was slower than phage propagation, and no reduction of the bacterial population was observed. The inhibition of the phages associated with a reduction in phage adsorption, quantified to 99% at 10% plasma. S. aureus is known to bind multiple coagulation factors, resulting in the formation of aggregates and blood clots that might protect the bacterium from the phages. Here, we show that purified fibrinogen at a sub-physiological concentration of 0.4 mg/ml is sufficient to impair phage activity. In contrast, dissolution of the clots by tissue plasminogen activator (tPA) partially restored phage activity. Consistent with these in vitro findings, phage treatment did not reduce bacterial burdens in a neutropenic mouse S. aureus thigh infection model. In summary, phage treatment of S. aureus infections inside the body may be fundamentally challenging, and more investigation is needed prior to proceeding to in-human trials., (© 2023. Springer Nature Limited.)

Introduction: New Zealand (NZ) has high rates of pediatric acute hematogenous osteomyelitis (AHO) with males and children of Pasifika and Māori ethnicity overrepresented., Aims: To update the incidence of Pediatric AHO over 10 years, identifying trends in presentation, organisms, treatment, and outcomes., Methods: A 10-year retrospective review of children aged 6 weeks to 15 years admitted with Pediatric AHO across two centers from 2008 to 2017. Demographic data, features of presentation, investigations, management, and complications were collected. Incidence was calculated from census data. Data were compared with our osteomyelitis database from the previous decade. (1)., Results: 796 cases were identified. The incidence was 18 per 100,000 per annum. The average age was 7.7 years. Pasifika and Māori children are overrepresented (57%). 370 children (51%) came from low socioeconomic areas. Methicillin-sensitive Staphylococcus aureus was the most common pathogen (87%). Methicillin-resistant Staphylococcus aureus (MRSA) rates are low (4.4%). Forty-four (5.5%) children were admitted to the Pediatric Intensive Care Unit (PICU) with 9% mortality. The mean duration of antibiotics was 40 days. 325 children (41%) had surgery. Chronic infection has increased from 1.7% to 5.7%., Conclusions: NZ has high rates of AHO, however, the incidence has decreased from the previous decade. Males, those in low socioeconomic areas, Pasifika and Māori have high disease burden. The use of MRI as a diagnostic modality has increased. Future studies should focus on improving treatment via prospective analysis and reporting long-term morbidity to improve outcomes for children with severe disease and reduce rates of chronic infection., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purposes: The purpose of this study was to present and analyze the etiologic factors, clinical manifestations, bacteriology, and treatment outcomes of nasal septal abscess in a large cohort of adult patients., Material and Methods: Retrospective analysis., Results: 36 adult patients, age from 19 to 85 (mean age, 51.83), with nasal septal abscesses were treated at Ear Nose Throat Hospital of Ho Chi Minh City from January 2020 to August 2022. The most common symptoms were nasal obstruction (75 %), headache/facial pain (58.33 %). Etiologic factors were found in 83.33 % of cases with the most common were diabetes mellitus (47.22 %), nose-picking (44.44 %). 75 % of cases had positive bacterial culture, of which 70.37 % were Staphylococcus aureus. Septal abscess was successfully treated in all cases using our treatment protocol, which involved an extended modified Killian's incision, irrigation with 1 % poviodine, placement of gauze in the abscess pocket, and nasal packing with Merocels., Conclusions: Diabetes and nose-picking were the most common etiologic factors; Staphylococcus aureus was the most common organism of nasal septal abscess in our study. Our treatment protocol is safe and effective., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

The issue of antibiotic resistance in healthcare worldwide has led to a pressing need to explore and develop alternative approaches to combat infectious diseases. Among these methods, phage therapy has emerged as a potential solution to tackle this growing challenge. Virulent phages of the Herelleviridae family, known for their ability to cause lysis of Staphylococcus aureus , a clinically significant pathogen frequently associated with multidrug resistance, have proven to be one of the most effective viruses utilized in phage therapy. In order to utilize phages for therapeutic purposes effectively, a thorough investigation into their physiology and mechanisms of action on infected cells is essential. The use of omics technologies, particularly total RNA sequencing, is a promising approach for analyzing the interaction between phages and their hosts, allowing for the assessment of both the behavior of the phage during infection and the cell's response. This review aims to provide a comprehensive overview of the physiology of the Herelleviridae family, utilizing existing analyses of their total phage transcriptomes. Additionally, it sheds light on the changes that occur in the metabolism of S. aureus when infected with virulent bacteriophages, contributing to a deeper understanding of the phage-host interaction.

Background: Infective arthritis is an orthopaedic surgical emergency. Staphylococcus aureus remains the commonest causative bacteria across all age groups. Prevotella spp. as a cause of infective arthritis is extremely rare., Case Report: We present our case of a 30-year-old African male patient who presented with mild signs of infective arthritis of the left hip. His risk factors were his background retroviral disease, intravenous drug abuse, and a previous episode of left hip arthrotomy which healed expectantly with intervention. The current presentation was treated with arthrotomy of the hip, fluid lavage, and skeletal traction based on our clinical findings and the rarity of the presentation was seen to be mobilising non-weight bearing with crutches, and pain-free on the left hip., Conclusion: A high index of suspicion for Prevotella Septic Arthritis (PSA) should be exercised when treating infective arthritis patients with background joint arthropathies, and intravenous drug abuse, especially in individuals with significant immunosuppression and/or recent tooth extraction. Fortunately, although rare an entity, good outcomes can be expected with early diagnosis and classic treatment principles of joint decompression and lavage as well as guided antibiotic therapy., (© 2023. The Author(s).)

Prosthetic valve endocarditis (PVE) remains a serious condition with a high mortality rate. Precise identification of the PVE-associated pathogen/s and their virulence is essential for successful therapy and patient survival. The commonly described PVE-associated pathogens are staphylococci, streptococci, and enterococci, with Staphylococcus aureus being the most frequently diagnosed species. Furthermore, multi-drug resistance pathogens are increasing in prevalence and continue to pose new challenges mandating a personalized approach. Blood cultures in combination with echocardiography are the most common methods to diagnose PVE, often being the only indication, it exists. In many cases, the diagnostic strategy recommended in the clinical guidelines does not identify the precise microbial agent, and frequently, false-negative blood cultures are reported. Despite the fact that blood culture findings are not always a good indicator of the actual PVE agent in the valve tissue, only a minority of re-operated prostheses are subjected to microbiological diagnostic evaluation. In this review, we focus on the diversity and the complete spectrum of PVE-associated bacterial, fungal, and viral pathogens in blood and prosthetic heart valve, their possible virulence potential, and their challenges in making a microbial diagnosis. We are curious to understand if the unacceptable high mortality of PVE is associated with the high number of negative microbial findings in connection with a possible PVE. Herein, we discuss the possibilities and limits of the diagnostic methods conventionally used and make recommendations for enhanced pathogen identification. We also show possible virulence factors of the most common PVE-associated pathogens and their clinical effects. Based on blood culture, molecular biological diagnostics, and specific valve examination, better derivations for the antibiotic therapy as well as possible preventive intervention can be established in the future., Competing Interests: Conflict of interest: There is no conflicts of interest of the authors who worked on this publication., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Phage therapy has been successfully used as an experimental therapy in the treatment of multidrug-resistant strains of Staphylococcus aureus (MDRSA)-caused skin infections and is seen as the most promising alternative to antibiotics. However, in recent years a number of reports indicating that phages can interact with eukaryotic cells emerged. Therefore, there is a need to re-evaluate phage therapy in light of safety. It is important to analyze not only the cytotoxicity of phages alone but also the impact their lytic activity against bacteria may have on human cells. As progeny virions rupture the cell wall, lipoteichoic acids are released in high quantities. It has been shown that they act as inflammatory agents and their presence could lead to the worsening of the patient's condition and influence their recovery. In our work, we have tested if the treatment of normal human fibroblasts with staphylococcal phages will influence the metabolic state of the cell and the integrity of cell membranes. We have also analyzed the effectiveness of bacteriophages in reducing the number of MDRSA attached to human fibroblasts and the influence of the lytic activity of phages on cell viability. We observed that, out of three tested anti- Staphylococcal phages-vB&#95;SauM-A, vB&#95;SauM-C and vB&#95;SauM-D-high concentrations (10 9 PFU/mL) of two, vB&#95;SauM-A and vB&#95;SauM-D, showed a negative impact on the viability of human fibroblasts. However, a dose of 10 7 PFU/mL had no effect on the metabolic activity or membrane integrity of the cells. We also observed that the addition of phages alleviated the negative effect of the MDRSA infection on fibroblasts' viability, as phages were able to effectively reduce the number of bacteria in the co-culture. We believe that these results will contribute to a better understanding of the influence of phage therapy on human cells and encourage even more studies on this topic.

Introduction: Staphylococcus aureus (SA) is a major human bacterial pathogen increasingly refractory to antibiotics. Given the dearth of novel antibiotics in the developmental pipeline, we require concerted efforts at optimizing novel antimicrobial approaches. One promising option is the utilization of bacteriophage (phage) therapy, which has been resurrected as a viable clinical therapeutic. Specifically, an expanded library of phages targeting SA is desired. We surmised that SA-targeting phages would be readily accessible as a major component of the cutaneous microbiome. Specifically, we sought to discern if easily accessible (convenient) and discrete anatomic locations, including the nares, axilla, fingernails, toenails, and web spaces, could provide intact phages via a noninvasive, expedient procedure involving swabbing., Methods: One hundred subjects participated in systematic skin swab specimen collections. Pooled samples were subject to phage harvesting utilizing the soft agar overlay technique. The approval was secured from the Naval Medical Research Center Institutional Review Board (NMRC 2018.0004 FWA00000152). We utilized the same procedures from known samples containing SA-targeting phages. As another positive control, we employed the same swab and acquired samples from an active wound infection., Results: As anticipated, there were no adverse events, and the procedure was successfully implemented within the projected 10-minute duration. No phages were identified exploiting this methodology. Positive controls from various environmental samples identified SA-targeting phages as did the wound effluent sample., Conclusions: Skin swabbing at multiple anatomic sites from 100 adults yielded insufficient biomass for phage recovery. The negative results provide helpful information for future phage isolation attempts. The lessons learned on why this study failed to isolate phages can be easily utilized by others. With a desire to increase our SA-targeting phage library in pursuit of future clinical trials, and acknowledging the paucity of these phages accessible via traditional recovery from environmental sources, we will next acquire large volumes of wound effluent from confirmed infected wounds with SA to optimize the biomass for phage recovery., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Combating multi-drug resistant bacterial infections should be a universal urgency. The gram- positive Staphylococcus aureus (S. aureus) bacteria are generally harmless; healthy people frequently have them on their skin and nose. These bacteria, for the most part, produce no difficulties or only minor skin diseases. Antibiotics and cleansing of the affected region are usually the treatments of choice. S. aureus can become virulent causing serious infections that may lead to pustules to sepsis or death. Normally, it is thought that antibiotics may solve problems concerning bacterial infection; but unfortunately, Staphylococci have evolved mechanisms to resist drugs. Methicillin-Resistant Staphylococcus aureus (MRSA); both in hospitals and in the community, infections are evolving into dangerous pathogens. Health care practitioners may need to use antibiotics with more adverse effects to treat antibiotic-resistant S. aureus infections. Amid existing efforts to resolve this problem, phage therapy proposes a hopeful alternate to face Staphylococcal infections. When the majority of antibiotics have failed to treat infections caused by multidrug-resistant bacteria, such as methicillin- and vancomycin-resistant S. aureus, phage therapy may be an option. Here, we appraise the potential efficacy, current knowledge on bacteriophages for S. aureus, experimental research and information on their clinical application, and limitations of phage therapy for S. aureus infections., (Copyright © 2023. Published by Elsevier Inc.)

There is widespread interest in using obligately lytic bacteriophages ("phages") to treat human bacterial infections. Among Staphylococcus aureus infections, the USA300 lineage is a frequent cause of invasive disease. We observed that phage K, a model S. aureus myophage, exhibits temperature-sensitive growth on USA300 strains, with the wild-type phage providing poorer growth suppression in broth and forming smaller and fainter plaques at 37 °C vs. 30 °C. We isolated 65 mutants of phage K that had improved plaquing characteristics at 37 °C when compared to the parental phage. In all 65 mutants, this phenotype was attributable to loss-of-function (LoF) mutations in gp102 , which encodes a protein of unknown function that has homologs only among the Herelleviridae (SPO1-like myophages infecting gram-positive bacteria). Additional experiments with representative mutants consistently showed that the temperature-sensitive plaque phenotype was specific to USA300 MRSA strains and that Gp102 disruption was correlated with improved suppression of bacterial growth in broth and improved antibacterial activity in a mouse model of upper respiratory tract infection. The same genotype and in vitro phenotypes could be replicated in close relatives of phage K. Gp102 disruption did not have a detectable effect on adsorption but did delay cell culture lysis relative to wild-type under permissive infection conditions, suggesting that gp102 conservation might be maintained by selective pressure for more rapid replication. Expression of gp102 on a plasmid was toxic to both an MSSA and a USA300 MRSA strain. Molecular modeling predicts a protein with two helix-turn-helix domains that displays some similarity to DNA-binding proteins such as transcription factors. While its function remains unclear, gp102 is a conserved gene that is important to the infection process of Kayvirus phages, and it appears that the manner in which USA300 strains defend against them at 37 °C can be overcome by gp102 LoF mutations.

Infections involving antibiotic resistant Staphylococcus aureus ( S. aureus ) represent a major challenge to successful treatment. Further, although bacteriophages (phages) could be an alternative to antibiotics, there exists a lack of correlation in phage susceptibility results between conventional in vitro and in vivo assays. This discrepancy may hinder the potential implementation of bacteriophage therapy. In this study, the susceptibility of twelve S. aureus strains to three commercial phage cocktails and two single phages was assessed. These S. aureus strains (including ten clinical isolates, five of which were methicillin-resistant) were compared using four assays: the spot test, efficiency of plating (EOP), the optical density assay (all in culture media) and microcalorimetry in human serum. In the spot test, EOP and optical density assay, all cocktails and single phages lysed both methicillin susceptible and methicillin resistant S. aureus strains. However, there was an absence of phage-mediated lysis in high concentrations of human serum as measured using microcalorimetry. As this microcalorimetry-based assay more closely resembles in vivo conditions, we propose that microcalorimetry could be included as a useful addition to conventional assays, thereby facilitating more accurate predictions of the in vivo susceptibility of S. aureus to phages during phage selection for therapeutic purposes.

Staphylococcus virus ΦSA012 has a wide host range and efficient lytic activity. Here, we assessed the biological stability of ΦSA012 against temperature, freeze-thawing, and pH to clinically apply the phage. In addition, inoculation of ΦSA012 through i.p. and i.v. injections into mice revealed that phages were reached the limit of detection in serum and accumulated notably spleens without inflammation at 48 h post-inoculation. Furthermore, inoculation of ΦSA012 through s.c. injections in mice significantly induced IgG, which possesses neutralizing activity against ΦSA012 and other Staphylococcus viruses, ΦSA039 and ΦMR003, but not Pseudomonas viruses ΦS12-3 and ΦR18 or Escherichia viruses T1, T4, and T7 in vitro. Immunoelectron microscopic analysis showed that purified anti-phage IgG recognizes the long-tail fiber of staphylococcus viruses. Although S. aureus inoculation resulted in a 25% survival rate in a mouse i.p. model, ΦSA012 inoculation (i.p.) improved the survival rate to 75%; however, the survival rate of ΦSA012-immunized mice decreased to less than non-immunized mice with phage i.v. injection at a MOI of 100. These results indicated that ΦSA012 possesses promise for use against staphylococcal infections but we should carefully address the appropriate dose and periods of phage administration. Our findings facilitate understandings of staphylococcus viruses for phage therapy., (© 2022. The Author(s).)

Staphylococcus aureus is the main aetiologic agent of osteoarticular infections (OAIs) in paediatric patients. The aim of this prospective unicenter study was to describe the phenotypic and genotypic characteristics of S. aureus isolates obtained from OAIs in paediatric patients admitted to tertiary care hospital. Through a surveillance program called OsteoCode , a multidisciplinary team was created and we identified 27 patients with OAIs caused by S. aureus from 2019 to 2021. The susceptibility profile, virulence factors, biofilm formation, pulsed-field gel electrophoresis (PFGE), clonal complex (CC) and sequence type (ST) were determined. In addition, the clinical characteristics and evolution of the patients presented six months after the diagnosis of OAIs were described. Ninety-two percent of the isolates were methicillin-sensitive S. aureus (MSSA). In methicillin-resistant S. aureus (MRSA), SCC mec- II and SCC mec- V were detected. The pvl gene was only observed in MSSA (18.5%) and was associated with highest fever ( p =0.015), multiple localization ( p= 0.017), and soft tissue sites of infection beyond the bone (pyomyositis, pulmonary abscess) ( p= 0.017). Biofilm formation was detected in 55.6% of isolates. The most common CC were CC5 and CC30 which represent the most common linages for bone and joint infections worldwide. The isolates were distributed in different STs, and ST672 was predominant. MRSA were associated with a longer duration of intravenous treatment and a prolonged hospital stay ( p= 0.023). Recurrent infection occurred in five children and orthopaedic complications in 33.3% of patients. This is the first study that reflects the epidemiology of S. aureus in OAIs in paediatric patients in Mexico; a clear predominance of MSSA distributed in different STs was observed. Our findings highlight that a multidisciplinary team is required for the diagnosis and treatment of OAIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aguilar-Gómez, Merida-Vieyra, Isunza-Alonso, Morales-Pirela, Colín-Martínez, Juárez-Benítez, García de la Puente and Aquino-Andrade.)

Background: Staphylococcus aureus (S. aureus) is one of the major causes of bovine mastitis with significant economic losses around the worldwide. The emergence of multidrug-resistant (MDR), methicillin-resistant (MRSA) and biofilm-producing strains of S. aureus challenges the treatment strategies based on the antibiotic application. Today, alternative or combinational treatment options such as bacteriophage application has received much attention. The goal of the present study was to focus on isolation and evaluation of the efficacy of bacteriophages with specific lytic activity against S. aureus strains with low cure rates (MDR, MRSA and biofilm-producing strains)., Results: In the present study, two phages belonging to the Podoviridae family with specific lytic activity against S. aureus were isolated from the sewage of dairy farms and designated as Staphylococcus phage M8 and Staphylococcus phage B4. Latent period and burst size for Staphylococcus phage M8 (70 min, 72 PFU/cell) and Staphylococcus phage B4 (30 min, 447 PFU/cell) were also defined. Our results revealed the susceptibility of MDR (4/20; 20%), MRSA (4/13; 30.8%) and biofilm-producing (1/10; 10%) strains to Staphylococcus phage M8. Moreover, one biofilm-producing strain (1/10; 10%) was susceptible to Staphylococcus phage B4. Furthermore, both phages kept their lytic activity in milk. They reduced the S. aureus population by about 3 logs in cultured milk after 8 h of incubation., Conclusion: In conclusion, it seems that both phages had the potential to serve as biological control agents alone or in combination with other agents such as antibiotics against infections induced by S. aureus. However, further studies are needed to investigate the efficacy of these phages in vivo., (© 2022. The Author(s).)

It is difficult to effectively treat bacterial osteomyelitis using photothermal therapy or photodynamic therapy due to poor penetration of light. Here, a microwave (MW)-excited magnetic composite of molybdenum disulfide (MoS 2 ) / iron oxide (Fe 3 O 4 ) is reported for the treatment of bacteria-infected osteomyelitis. In in vitro and in vivo experiments, MoS 2 /Fe 3 O 4 is shown to effectively eradicate bacteria-infected mouse tibia osteomyelitis, due to MW thermal enhancement and reactive oxygen species (ROS) ( 1 O 2 and ·O 2 - ) production under MW radiation. In addition, the mechanism of MW heat generation is proposed by MW network vector analysis. By the density functional theory and finite element method, the ROS generation mechanism is proposed. The synergy or conductive network between dielectric MoS 2 and magnetic Fe 3 O 4 can reach both enhancement of the dielectric and magnetic attenuation capability. In addition, abundant interfaces are generated to enhance the attenuation of electromagnetic waves by MoS 2 and Fe 3 O 4, introducing multiple reflections and interfacial polarization. Therefore, MoS 2 /Fe 3 O 4 has excellent MW absorption ability based on the synergy or conductive network between MoS 2 and magnetic Fe 3 O 4 as well as multiple dielectric reflections and interfacial polarization., (© 2022 Wiley-VCH GmbH.)

Objective: Diabetic foot infection (DFI) represents a major healthcare burden, for which treatment is challenging owing to the pathophysiological alterations intrinsic to diabetes and the alarming increase of antimicrobial resistance. Novel therapies targeting DFI are therefore a pressing research need for which proper models of disease are required., Results: Here, we present an optimized diabetic mouse model of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds, that resemble key features of DFI, such as pathogen invasion through wound bed and surrounding tissue, necrosis, persistent inflammation and impaired wound healing. Thus, in a time-efficient manner and using simple techniques, this model represents a suitable approach for studying emerging therapies targeting DFI caused by MRSA., (© 2022. The Author(s).)

Bacteriophages have been investigated for clinical utility, both as diagnostic tools and as therapeutic interventions. In order to be applied successfully, a detailed understanding of the influence of the human matrix on the interaction between bacteriophage and the host bacterium is required. In this study, a cocktail of luciferase bacteriophage reporters was assessed for functionality in a matrix containing human serum and spiked with Staphylococcus aureus . The inhibition of signal and loss of sensitivity was evident with minimal amounts of serum. This phenotype was independent of bacterial growth and bacteriophage viability. Serum-mediated loss of signal was common, albeit not universal, among S. aureus strains. Immunoglobulin G was identified as an inhibitory component and partial inhibition was observed with both the f(ab') 2 and Fc region. A modified bacteriophage cocktail containing recombinant protein A was developed, which substantially improved signal without the need for additional sample purification. This study highlights the importance of assessing bacteriophage activity in relevant host matrices. Furthermore, it identifies an effective solution, recombinant protein A, for promoting bacteriophage-based detection of S. aureus in matrices containing human serum.

Background: Infective endocarditis (IE) is a potentially lethal disease for adults with congenital heart disease (ACHD). Staphylococcus aureus (SA) is one of the commonest pathogens, identified in patients with ACHD and IE. This study aims to analyse the epidemiology, clinical characteristics and in-hospital management of IE due to SA (SAIE) in ACHD., Methods: This is a single center retrospective study on documented episodes of SAIE in ACHD patients, treated at the Royal Brompton Hospital between 1999 and February 2020., Results: Thirty-seven ACHD patients had an episode of SAIE (mean age 35.5 ± 14.9 years). More than half (51.3%), had a cardiac lesion of at least moderate complexity, with left ventricular outflow tract lesions being the most frequent. Twenty-four (64.9%) patients had a history of at least one previous open-heart surgery, and prosthetic material was used in 20 patients. A predisposing event was identified in 11 episodes (29.7%). Surgery was performed during the same admission in 24 (64.9%) patients, with early surgery (≤ 7 days from admission) performed in 12 patients. Early operation was associated with a shorter in-hospital stay compared to a later operation during the same admission or medical management [28.5 (IQR 23) vs. 43.5 (IQR 30) days, P = 0.028]. In-hospital mortality was 8.1%. Renal dysfunction at admission was associated with in-hospital multiorgan complications and/or death (OR 7.50, 95% CI, 1.18-47.67, P = 0.03)., Conclusion: SAIE remains a life-threatening complication, necessitating cardiac surgery in the majority of ACHD patients. Ongoing educational investment on prevention and timely SAIE detection is warranted., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Osteomyelitis remains one of the greatest risks in orthopaedic surgery. Although many organisms are linked to skeletal infections, Staphylococcus aureus remains the most prevalent and devastating causative pathogen. Important discoveries have uncovered novel mechanisms of S. aureus pathogenesis and persistence within bone tissue, including implant-associated biofilms, abscesses and invasion of the osteocyte lacuno-canalicular network. However, little clinical progress has been made in the prevention and eradication of skeletal infection as treatment algorithms and outcomes have only incrementally changed over the past half century. In this Review, we discuss the mechanisms of persistence and immune evasion in S. aureus infection of the skeletal system as well as features of other osteomyelitis-causing pathogens in implant-associated and native bone infections. We also describe how the host fails to eradicate bacterial bone infections, and how this new information may lead to the development of novel interventions. Finally, we discuss the clinical management of skeletal infection, including osteomyelitis classification and strategies to treat skeletal infections with emerging technologies that could translate to the clinic in the future., (© 2022. Springer Nature Limited.)

Kayviruses are polyvalent broad host range staphylococcal phages with a potential to combat staphylococcal infections. However, the implementation of rational phage therapy in medicine requires a thorough understanding of the interactions between bacteriophages and pathogens at omics level. To evaluate the effect of a phage used in therapy on its host bacterium, we performed differential transcriptomic analysis by RNA-Seq from bacteriophage K of genus Kayvirus infecting two Staphylococcus aureus strains, prophage-less strain SH1000 and quadruple lysogenic strain Newman. The temporal transcriptional profile of phage K was comparable in both strains except for a few loci encoding hypothetical proteins. Stranded sequencing revealed transcription of phage noncoding RNAs that may play a role in the regulation of phage and host gene expression. The transcriptional response of S. aureus to phage K infection resembles a general stress response with differential expression of genes involved in a DNA damage response. The host transcriptional changes involved upregulation of nucleotide, amino acid and energy synthesis and transporter genes and downregulation of host transcription factors. The interaction of phage K with variable genetic elements of the host showed slight upregulation of gene expression of prophage integrases and antirepressors. The virulence genes involved in adhesion and immune evasion were only marginally affected, making phage K suitable for therapy. IMPORTANCE Bacterium Staphylococcus aureus is a common human and veterinary pathogen that causes mild to life-threatening infections. As strains of S. aureus are becoming increasingly resistant to multiple antibiotics, the need to search for new therapeutics is urgent. A promising alternative to antibiotic treatment of staphylococcal infections is a phage therapy using lytic phages from the genus Kayvirus. Here, we present a comprehensive view on the phage-bacterium interactions on transcriptomic level that improves the knowledge of molecular mechanisms underlying the Kayvirus lytic action. The results will ensure safer usage of the phage therapeutics and may also serve as a basis for the development of new antibacterial strategies.

Importance: Staphylococcus aureus bacteremia (SAB) is a common and potentially severe infectious disease (ID). Retrospective studies and derived meta-analyses suggest that bedside infectious disease consultation (IDC) for SAB is associated with improved survival; however, such IDCs might not always be possible because of the lack of ID specialists, particularly at nonacademic hospitals., Objectives: To investigate whether unsolicited telephone IDCs (triggered by an automated blood stream infection reporting system) to nonacademic hospitals improved 30-day all-cause mortality in patients with SAB., Design, Setting, and Participants: This patient-blinded, multicenter, interventional, cluster randomized, controlled, crossover clinical trial was conducted in 21 rural, nonacademic hospitals in Thuringia, Germany. From July 1, 2016, to December 31, 2018, 1029 blood culture reports were assessed for eligibility. A total of 386 patients were enrolled, whereas 643 patients were not enrolled for the following reasons: death before enrollment (n = 59); palliative care (n = 41); recurrence of SAB (n = 9); discharge from the hospital before enrollment (n = 77); age younger than 18 years (n = 5); duplicate report from a single patient (n = 26); late report (n = 17); blood culture reported during the washout phase (n = 48); and no signed informed consent for other or unknown reasons (n = 361)., Interventions: During the ID intervention phase, ID specialists from Jena University Hospital provided unsolicited telephone IDCs to physicians treating patients with SAB. During the control phase, patients were treated according to local standards. Crossover was performed after including 15 patients or, at the latest, 1 year after the first patient was included., Main Outcomes and Measures: Thirty-day all-cause mortality., Results: A total of 386 patients (median [IQR] age, 75 [63-82] years; 261 [67.6%] male) were included, with 177 randomized to the IDC group and 209 to the control group. The 30-day all-cause mortality rate did not differ between the IDC and control groups (relative risk reduction [RRR], 0.12; 95% CI, -2.17 to 0.76; P = .81). No evidence was found of a difference in secondary outcomes, including 90-day mortality (RRR, 0.17; 95% CI, -0.59 to 0.57; P = .62), 90-day recurrence (RRR, 0.10; 95% CI, -2.51 to 0.89; P = .89), and hospital readmission (RRR, 0.04; 95% CI, -0.63 to 0.48; P = .90). Exploratory evidence suggested that indicators of quality of care were potentially realized more often in the IDC group than in the control group (relative quality improvement, 0.16; 95% CI, 0.08-0.26; P = .01)., Conclusions and Relevance: In this cluster randomized clinical trial, unsolicited telephone IDC, although potentially enhancing quality of care, did not improve 30-day all-cause mortality in patients with SAB., Trial Registration: drks.de Identifier: DRKS00010135.

The high infection and mortality rate of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the urgent development of new treatment strategies. Bacteriophages (phages) have several advantages compared to antibiotics for the treatment of multi-drug-resistant bacterial infections, and thus provide a promising alternative to antibiotics. Here, S. aureus phages were isolated from patients and environmental sources. Phages were characterized for stability, morphology and genomic sequence and their bactericidal activity against the biofilm form of methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA was investigated. Four S. aureus phages were isolated and tested against 51 MSSA and MRSA clinical isolates and reference strains. The phages had a broad host range of 82−94% individually and of >98% when combined and could significantly reduce the viability of S. aureus biofilms. The phages had a latent period of ≤20 min and burst size of >11 plaque forming units (PFU)/infected cell. Transmission electron microscopy (TEM) identified phages belonging to the family of Myoviridae. Genomic sequencing indicated the lytic nature of all four phages, with no identified resistance or virulence genes. The 4 phages showed a high complementarity with 49/51 strains (96%) sensitive to at least 2/4 phages tested. Furthermore, the frequency of bacteriophage insensitive mutant (BIM) generation was lower when the phages were combined into the phage cocktail APTC-C-SA01 than for bacteria exposed to each of the phages alone. In conclusion, APTC-C-SA01, containing four lytic S. aureus phages has the potential for further development as a treatment against MSSA and MRSA infections.

We assessed the incidence of aortic valve surgery intervention in the treatment of infective endocarditis (IE) after transcatheter aortic valve replacement (TAVR) and compared the characteristics and outcomes of surgical intervention versus medical management alone in this cohort using a nationwide data set. We identified all the hospitalizations in patients undergoing TAVR who developed IE within 1-year (i.e., early IE) of the procedure from 2014 to 2017 using the Nationwide Readmission Database (NRD). The primary outcomes of the study were in-hospital mortality. A total of 906 hospitalizations were identified for IE amongst the TAVR patients from 2014 to 2017 of which 20 (2.21%) underwent aortic valve surgery during the hospitalization. Patients undergoing surgery were younger, more likely to have Staphylococcus aureus endocarditis, cardiogenic shock, and acute kidney injury (AKI) during the hospitalization. There were no significant differences in in-hospital mortality (9.9% vs. 12.4%, p = 0.824; adjusted odds ratio (aOR): 0.26 (0.01-1.58), p = 0.223) and 30-day readmissions. However, the length of stay and hospitalization costs were higher in surgical intervention group. The important predictors of in-hospital mortality in TAVR-related IE patients were dialysis during IE hospitalization, AKI, cardiogenic shock, Staphylococcus aureus endocarditis, stroke, and female sex. The utilization of surgical management for IE post-TAVR during the index hospitalization is low, and there is no significant mortality benefit with surgical intervention as compared with the medical management., (© 2022 Wiley Periodicals LLC.)

We reviewed all cases of Panton-Valentine leukocidin-producing Staphylococcus aureus (PVL-SA) bacteremia in Danish children between 2016 and 2021. We found 2 fatal cases with preceding viral prodrome due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the usual benign course of SARS-CoV-2 infection in children, awareness of possible superinfection with PVL-SA in a child with rapid deterioration is crucial to ensure adequate treatment, including antimicrobial drugs with antitoxin effect., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The primary aim of this study was to evaluate the efficacy of phage against mastitis induced by drug-resistant S. aureus in a mouse model. In this study, five S. aureus phages-4086-1, 4086-2, 4086-3, 4086-4, and 4086-6-were isolated from milk samples secreted by mastitis cows. Transmission electron microscopy showed that all the five phages had icosahedral heads and short non-contractile tails, which are typical characteristics of the family Podoviridae. All these phages were species-specific against S. aureus . The one-step growth curve showed a short latency period (10-20 min) and high burst size (up to 400 PFU/infected cell). To evaluate the effectiveness of the phage 4086-1 in the treatment against mastitis, a mouse model of mastitis was challenged with drug-resistant S. aureus . The results showed the proliferation of S. aureus in the mammary glands was significantly inhibited after treating by phage 4086-1. The concentrations of TNF-α and IL-6 decreased significantly, which demonstrated the phages could effectively alleviate the inflammatory responses. Furthermore, the histopathological analysis showed that inflammatory infiltration in the mammary glands was significantly reduced. These results demonstrate that phage may be a promising alternative therapy against mastitis caused by drug-resistant S. aureus .

Infections of orthopaedic implants, such as fracture fixation devices and total-joint prostheses, are devastating complications. Staphylococcus aureus (S. aureus) is a predominant pathogen causing orthopaedic-implant biofilm infections that can also internalise and persist in osteoblasts, thus resisting antibiotic therapy. Bacteriophages are a promising alternative treatment approach. However, data on the activity of bacteriophages against S. aureus, especially during intracellular growth, and against in vivo biofilm formation on metals are scarce. Therefore, the present study evaluated the in vitro efficacy of S. aureus bacteriophage 191219, alone as well as in combination with gentamicin and rifampicin, to eradicate S. aureus strains in their planktonic stage, during biofilm formation and after internalisation into osteoblasts. Further, the invertebrate model organism Galleria mellonella was used to assess the activity of the bacteriophage against S. aureus biofilm on metal implants with and without antibiotics. Results demonstrated the in vitro efficacy of bacteriophage 191219 against planktonic S. aureus. The phage was also effective against in vitro S. aureus biofilm formation in a dose-dependent manner and against S. aureus internalised in an osteoblastic cell line. Transmission electron microscopy (TEM) analysis showed bacteriophages on S. aureus inside the osteoblasts, with the destruction of the intracellular bacteria and formation of new bacteriophages. For the Galleria mellonella infection model, single administration of phage 191219 failed to show an improvement in survival rate but appeared to show a not statistically significant enhanced effect with gentamicin or rifampicin. In summary, bacteriophages could be a potential adjuvant treatment strategy for patients with implant-associated biofilm infections.