Advances in the targeted theragnostics of osteomyelitis caused by Staphylococcus aureus.

Bone infections caused by Staphylococcus aureus may lead to an inflammatory condition called osteomyelitis, which results in progressive bone loss. Biofilm formation, intracellular survival, and the ability of S. aureus to evade the immune response result in recurrent and persistent infections that present significant challenges in treating osteomyelitis. Moreover, people with diabetes are prone to osteomyelitis due to their compromised immune system, and in life-threatening cases, this may lead to amputation of the affected limbs. In most cases, bone infections are localized; thus, early detection and targeted therapy may prove fruitful in treating S. aureus-related bone infections and preventing the spread of the infection. Specific S. aureus components or overexpressed tissue biomarkers in bone infections could be targeted to deliver active therapeutics, thereby reducing drug dosage and systemic toxicity. Compounds like peptides and antibodies can specifically bind to S. aureus or overexpressed disease markers and combining these with therapeutics or imaging agents can facilitate targeted delivery to the site of infection. The effectiveness of photodynamic therapy and hyperthermia therapy can be increased by the addition of targeting molecules to these therapies enabling site-specific therapy delivery. Strategies like host-directed therapy focus on modulating the host immune mechanisms or signaling pathways utilized by S. aureus for therapeutic efficacy. Targeted therapeutic strategies in conjunction with standard surgical care could be potential treatment strategies for S. aureus-associated osteomyelitis to overcome antibiotic resistance and disease recurrence. This review paper presents information about the targeting strategies and agents for the therapy and diagnostic imaging of S. aureus bone infections.

Piperacillin/tazobactam-induced sudden severe thrombocytopenia in a patient with a pressure ulcer: a case report.

The standard treatment for an infected pressure ulcer (PU) with osteomyelitis is debridement, wound coverage and antibiotic administration. However, systemic administration of antibiotics in patients with osteomyelitis is controversial, and the optimal treatment duration for chronic osteomyelitis has not been standardised. We report a case of sudden severe thrombocytopenia induced by piperacillin/tazobactam (PIPC/TAZ) in a patient with PU-related osteomyelitis. A 57-year-old male patient with paraplegia, using a wheelchair full-time, presented to our plastic surgery department with infection of a stage IV hard-to-heal ischial PU. We surgically debrided the necrotising tissue and raised an ipsilateral biceps femoris musculocutaneous propeller flap for wound coverage. Polymicrobial infections, including Pseudomonas aeruginosa, were detected in the bone biopsy sample; therefore, systemic PIPC/TAZ was administered for the osteomyelitis. Unexpectedly, during the next 12 days of antibiotic administration, the patient's platelet count acutely dropped to 1×103/µl over three days. Based on a series of examinations, PIPC/TAZ was suspected to be the most likely cause of the severe thrombocytopenia. After drug discontinuation, the thrombocytopenia gradually improved. PIPC/TAZ is one of the most widely used antibiotic combinations in the plastic surgery field; it is conventionally administered for hard-to-heal wounds such as PUs and diabetic foot. The present case suggests that surgeons must take special precautions for patients undergoing PIPC/TAZ treatment. In this report, PIPC/TAZ-induced thrombocytopenia and the efficacy of antibiotic treatment for PU-related osteomyelitis are discussed in light of the available literature.

Cat-scratch disease: a rare cause of osteomyelitis.

Cat-scratch disease is a zoonosis caused by Bartonella henselae, characterised by regional lymphadenopathy. Rarer presentations, such as osteomyelitis, can occur.We present an adolescent girl with severe right lumbar pain and fever, without animal contacts or recent travels. On examination, pain on flexion of torso, movement limitation and marked lordosis were noted, but there were no inflammatory signs, palpable masses or lymph nodes. Serological investigations revealed elevated inflammatory markers. Imaging revealed a paravertebral abscess with bone erosion. Several microbiological agents were ruled out. After a second CT-guided biopsy, PCR for Bartonella spp was positive. At this point, the family recalled having a young cat some time before. Cat-scratch disease was diagnosed, and complete recovery achieved after treatment with doxycycline and rifampicin.Cat-scratch disease is a challenging diagnosis in the absence of typical features. However, B. henselae must be investigated if common pathogens are ruled out and response to therapy is poor.

Prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections.

Osteomyelitis is a devastating disease caused by microbial infection in deep bone tissue. Its high recurrence rate and impaired restoration of bone deficiencies are major challenges in treatment. Microbes have evolved numerous mechanisms to effectively evade host intrinsic and adaptive immune attacks to persistently localize in the host, such as drug-resistant bacteria, biofilms, persister cells, intracellular bacteria, and small colony variants (SCVs). Moreover, microbial-mediated dysregulation of the bone immune microenvironment impedes the bone regeneration process, leading to impaired bone defect repair. Despite advances in surgical strategies and drug applications for the treatment of bone infections within the last decade, challenges remain in clinical management. The development and application of tissue engineering materials have provided new strategies for the treatment of bone infections, but a comprehensive review of their research progress is lacking. This review discusses the critical pathogenic mechanisms of microbes in the skeletal system and their immunomodulatory effects on bone regeneration, and highlights the prospects and challenges for the application of tissue engineering technologies in the treatment of bone infections. It will inform the development and translation of antimicrobial and bone repair tissue engineering materials for the management of bone infections.

Nicotine promotes Staphylococcus aureus-induced osteomyelitis by activating the Nrf2/Slc7a11 signaling axis.

Although smoking is a significant risk factor for osteomyelitis, there is limited experimental evidence that nicotine, a key tobacco constituent, is associated with this condition, leaving its mechanistic implications uncharacterized. This study revealed that nicotine promotes Staphylococcus aureus-induced osteomyelitis by increasing Nrf2 and Slc7a11 expression in vivo and in vitro. Inhibition of Slc7a11 using Erastin augmented bacterial phagocytosis/killing capabilities and fortified antimicrobial responses in an osteomyelitis model. Moreover, untargeted metabolomic analysis demonstrated that Erastin mitigated the effects of nicotine on S. aureus-induced osteomyelitis by altering glutamate/glutathione metabolism. These findings suggest that nicotine aggravates S. aureus-induced osteomyelitis by activating the Nrf2/Slc7a11 signaling pathway and that Slc7a11 inhibition can counteract the detrimental health effects of nicotine.

Identification of pathogen composition in a Chinese population with iatrogenic and native vertebral osteomyelitis by using mNGS.

BACKGROUND: Early antimicrobial therapy is crucial regarding the prognosis of vertebral osteomyelitis, but early pathogen diagnosis remains challenging. OBJECTIVE: In this study, we aimed to differentiate the types of pathogens in iatrogenic vertebral osteomyelitis (IVO) and native vertebral osteomyelitis (NVO) to guide early antibiotic treatment. METHODS: A total of 145 patients, who had confirmed spinal infection and underwent metagenomic next-generation sequencing (mNGS) testing, were included, with 114 in the NVO group and 31 in the IVO group. Using mNGS, we detected and classified 53 pathogens in the 31 patients in the IVO group and 169 pathogens in the 114 patients in the NVO group. To further distinguish IVO from NVO, we employed machine learning algorithms to select serum biomarkers and developed a nomogram model. RESULTS: The results revealed that the proportion of the Actinobacteria phylum in the NVO group was approximately 28.40%, which was significantly higher than the 15.09% in the IVO group. Conversely, the proportion of the Firmicutes phylum (39.62%) in the IVO group was markedly increased compared to the 21.30% in the NVO group. Further genus-level classification demonstrated that Staphylococcus was the most common pathogen in the IVO group, whereas Mycobacterium was predominant in the NVO group. Through LASSO regression and random forest algorithms, we identified 5 serum biomarkers including percentage of basophils (BASO%), percentage of monocytes (Mono%), platelet volume (PCT), globulin (G), activated partial thromboplastin time (APTT) for distinguishing IVO from NVO. Based on these biomarkers, we established a nomogram model capable of accurately discriminating between the two conditions. CONCLUSION: The results of this study hold promise in providing valuable guidance to clinical practitioners for the differential diagnosis and early antimicrobial treatment of vertebral osteomyelitis.

Management of Chronic Osteomyelitis and Antibiotic Stewardship; An Effort to Delay the Post-Antibiotic Era.

OBJECTIVE: To develop an effective antimicrobial strategy for the management of chronic osteomyelitis. STUDY DESIGN: Observational study. Place and Duration of the Study: Departments of Microbiology and Orthopaedics, Combined Military Hospital Malir, Karachi, Pakistan, from January 2021 to February 2022. METHODOLOGY: Bone biopsies of 45 enrolled participants were taken for microbiological evaluation. Intravenous antibiotic therapy was begun as per empirical therapy based on the local antibiogram and antibiotic policy. Once the susceptibility pattern was available, targeted therapy started and continued for 28 to 42 days. Patients were evaluated based on inflammatory markers and clinical conditions for a minimum of six months to a maximum of one year. RESULTS:  Out of the 45 patients, the majority 29% were soldiers, 40% belonging to the age group of 31-60 years. The common predisposing factor was trauma/fractures followed by diabetes and implants leading to chronic sinus discharge and decubitus ulcers. The most commonly isolated organism was Staphylococcus aureus (38%) followed by Methicillin-resistant Staphylococcus aureus (MRSA) (31%). Cotrimoxazole and Rifampicin turned out to be good treatment options. Only 4.4% showed unsatisfactory prognosis, nonetheless, no mortality was observed during the course of treatment. CONCLUSION: In this study, highly resistant strains were observed with limited treatment options for chronic osteomyelitis, however, effective stewardship programmes with accurate diagnostic reporting and judicious use of antimicrobials can prevent overuse of the valuable resources. KEY WORDS: Antimicrobial stewardship, Osteomyelitis, Methicillin-resistant Staphylococcus aureus, Empirical therapy, Antimicrobial resistance.

Diagnostic efficacy and clinical impact of image-guided core needle biopsy of suspected vertebral osteomyelitis.

OBJECTIVES: The diagnostic yield and clinical impact of image-guided core needle biopsy (ICNB) of suspected vertebral osteomyelitis in adults is heterogenous in published studies owing to small sample sizes, indicating the need for large cohort studies. METHODS: A retrospective analysis of ICNBs was performed from 2010 to 2021 for patients with imaging findings consistent with vertebral osteomyelitis. For each biopsy, a series of factors were analyzed, as well as if histopathology was diagnostic of osteomyelitis and if microbiological cultures were positive. In addition, it was recorded in what way biopsy influenced clinical management regarding antimicrobial treatment. A multivariate statistical analysis was performed to evaluate the factors associated with yield. RESULTS: A total of 570 biopsies performed on 527 patients were included. A histopathologic diagnosis of osteomyelitis was made in 68.4% (359 of 525) of biopsies, and microbiological cultures were positive in 29.6% (169 of 570). Elevated erythrocyte sedimentation rate was positively associated with a histopathologic diagnosis of osteomyelitis (odds ratio [OR] =1.96, P = 0.007) and positive cultures from bone cores (OR = 1.02, P ≤0.001) and aspirate (OR = 1.02, P ≤0.001). Increased total core length was positively associated with a histopathologic diagnosis of osteomyelitis (OR = 1.81, P = 0.013) and positive cultures from bone cores (OR = 1.65, P = 0.049). Clinical management was affected by ICNB in 37.5% (214 of 570) of cases. CONCLUSIONS: In this large cohort, ICNB yielded approximately 30% positive cultures and changed clinical management in over one-third of the patients.

Collaborative approach to paediatric chronic non-bacterial osteomyelitis of the mandible: Great Ormond Street Hospital case series.

This paper outlines a 10-patient case series of chronic non-bacterial osteomyelitis (CNO) of the mandible at a tertiary paediatric hospital in the UK. Our findings highlight the homogeneous presenting signs and symptoms of an intermittently painful, swollen angle and ramus of the mandible. We present the typical laboratory investigative findings (normal inflammatory markers) and imaging appearances (sclerosis and periosteal oedema). Our paper outlines an investigation protocol, including recommendations for extraoral bone biopsies and systemic magnetic resonance imaging (MRI). We explain the importance of multidisciplinary care, with combined care by rheumatologists and infectious disease specialists. Finally we demonstrate the efficacy of our treatment algorithm for oral non-steroidal anti-inflammatory drugs (NSAIDs), and in those cases refractory to NSAIDS, intravenous pamidronate. This paper provides a useful addition to the literature by informing OMF surgeons of this rare condition and given the clinical equipoise in treatments, it can hopefully guide clinicians in an investigation pathway and management protocol.

18F-FDG PET imaging for treatment response assessment and management guidance in patients with skull base osteomyelitis.

OBJECTIVE: The objective of this study is to evaluate the role of hybrid 18F-FDG PET for treatment response assessment and management guidance in patients with skull base osteomyelitis. MATERIALS AND METHODS: Retrospectively, 33 patients, with at least a baseline and follow-up PET (computed tomography/MRI) scan, were included. Parameters like standardized uptake value (SUV) max, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) (initial, follow-up, percentage change) were analysed and outcomes based on 18F-FDG PET reports were classified into resolution (a), partial response (b), progression (c) and stable disease (d). The clinical course and response on anatomical imaging were also compared with 18F-FDG PET. RESULTS: There was mild correlation between initial SUV with ESR (0.338) and CRP (0.384). Moderate correlation was seen between follow-up SUV and CRP (0.619), percentage change in SUV max (PC SUV) with percentage change in ESR (0.456) and CRP (0.668). Mean PC SUV was 70% (a), 35% (b), -40% (c) and -18% (d), respectively. 48% (16/33) (resolution, progression, stable disease) patients had clear management change with 18F-FDG PET with either escalation or stopping of antibiotics/antifungals. Management decision in partial response group (52%, 17/33) was taken clinically. On retrospective PC SUV analysis, treatment continuation group (8 patients) showed 20% decrease, whereas the group that was only monitored further (9 patients) had 48% reduction in SUV. CONCLUSION: 18F-FDG PET showed a moderate association with clinical markers used in follow-up of patients with skull base osteomyelitis and is a reliable investigation for assessment of disease status. This can be used as a guide along with clinical evaluation for de-escalation of treatment.

Disseminated Cryptococcus neoformans infection involving multiple bones and lung in an immunocompetent patient: a case report.

BACKGROUND: Cryptococcal osteomyelitis is a rare and potentially serious condition, typically encountered in individuals with compromised immune systems. This case underscores the unusual occurrence of disseminated Cryptococcosis in an immunocompetent person, involving multiple bones and lungs, with Cryptococcus neoformans identified as the causative agent. CASE PRESENTATION: An Indonesian man, previously in good health, presented with a chief complaint of successive multiple bone pain lasting for more one month, without any prior history of trauma. Additionally, he reported a recent onset of fever. On physical examination, tenderness was observed in the left lateral chest wall and right iliac crest. Laboratory findings indicated mildly elevated inflammatory markers. A computed tomography (CT) scan of the chest revealed an ovoid solid nodule in the right lower lung and multifocal osteolytic lesions in the sternum, ribs, and humeral head. A magnetic resonance imaging (MRI) study of the sacrum showed multiple lesions in the bilateral iliac bone and the lower L4 vertebral body. Confirmation of Cryptococcal osteomyelitis involved a fine-needle biopsy and culture, identifying Cryptococcus neoformans in the aspirate. The patient responded positively to targeted antifungal treatments, leading to a gradual improvement in his condition. CONCLUSIONS: This case emphasizes the need to consider Cryptococcus neoformans osteomyelitis in immunocompetent patients with bone pain. A definitive diagnosis involves a fine-needle biopsy for pathology and culture, and prompt initiation of appropriate antifungal treatment has proven effective in preventing mortality.

Head-to-head comparison of multi-dose oritavancin and dalbavancin for complicated infections: A propensity score-matched analysis.

BACKGROUND: Oritavancin and dalbavancin are long-acting lipoglycopeptide antibiotics approved for the treatment of skin and skin structure infections. Recently, they have been used for outpatient antimicrobial therapy for complicated infections. No head-to-head studies exist for this purpose. OBJECTIVE: To compare outcomes of patients treated with multiple doses of oritavancin or dalbavancin for complicated infections. PATIENTS AND METHODS: This was a single-centre, retrospective cohort study evaluating adult patients who received two or more doses of lipoglycopeptides for complicated infections from February 2019 through December 2022. Patients receiving oritavancin were compared to dalbavancin after propensity score-matching. The primary endpoint was clinical success at 90 days. Other endpoints included: 30-day re-admission, 30-day mortality, adverse drug reactions (ADRs), and changes in white blood cell count and inflammatory markers after the first dose. RESULTS: After exclusions and propensity score-matching, 131 matched pairs (N = 262) were included in the analysis. Most patients were receiving lipoglycopeptide therapy for osteomyelitis. There was no significant difference in clinical success at 90 days in patients who received oritavancin compared to those who received dalbavancin (99 [76%] vs. 103 [79%], respectively; P = 0.556). There was no significant difference in secondary endpoints, however, there was a trend towards higher incidence of ADRs oritavancin compared to dalbavancin (9 [7%] vs. 2 [2%], respectively; P = 0.060) which led to more treatment discontinuation. CONCLUSION: There was no significant difference in efficacy between multi-dose oritavancin and dalbavancin for the treatment of complicated infections. Both agents were generally well tolerated; however, dalbavancin may be better tolerated when long-term treatment is warranted.

Clinical findings and outcome in goats with discospondylitis and vertebral osteomyelitis.

BACKGROUND: Vertebral infections, including vertebral osteomyelitis, septic physitis, and discospondylitis, are rarely reported in goats, and when reported, have been largely limited to necropsy case reports. OBJECTIVE: Describe clinical findings and outcome in goats with vertebral infections evaluated by computed tomography (CT). ANIMALS: Five goats with vertebral osteomyelitis, septic physitis, and discospondylitis evaluated by CT. METHODS: Retrospective case series. RESULTS: The most common presenting complaints were progressive weakness, paresis and recumbency. Three goats were tetraparetic and 2 goats had pelvic limb paraparesis. Clinicopathologic findings included leukocytosis, mature neutrophilia, and hyperfibrinogenemia. The most common vertebrae affected were C7-T1. All 5 goats had discospondylitis with or without vertebral osteomyelitis and septic physitis. Computed tomographic evidence of spinal cord compression was present in 4/5 goats. Medical management (antimicrobials, physical therapy, analgesia, supportive care) was attempted in 4 goats, and 1 goat was euthanized at the time of diagnosis. All 4 goats that were treated regained ambulatory ability and survived to hospital discharge. CONCLUSIONS AND CLINICAL IMPORTANCE: Despite severity of CT imaging findings, goats with discospondylitis, septic physitis, and vertebral osteomyelitis can successfully return to ambulatory function. Additional studies are required to determine ideal treatment regimens.

Non-vertebral Mycobacterium avium complex osteomyelitis in an immunocompetent patient.

Mycobacterium avium complex (MAC) is a ubiquitous soil pathogen that is an uncommon cause of diseases in immunocompetent patients. In this case, we describe the presentation of an otherwise healthy man in his 50s presenting with months of malaise and severe hip pain, with aspiration initially yielding no bacteria and presumed fastidious infection. He was treated with irrigation and debridement, surgical stabilisation of the femoral neck and conventional broad-spectrum antibiotics with final cultures diagnostic of MAC osteomyelitis. This case serves to demonstrate the importance of clinical suspicion and appropriate workup of this unusual case of MAC hip osteomyelitis in an otherwise immunocompetent patient.

Inflammatory Microenvironment-Responsive Hydrogels Enclosed with Quorum Sensing Inhibitor for Treating Post-Traumatic Osteomyelitis.

Non-antibiotic strategies are desperately needed to treat post-traumatic osteomyelitis (PTO) due to the emergence of superbugs, complex inflammatory microenvironments, and greatly enriched biofilms. Previously, growing evidence indicated that quorum sensing (QS), a chemical communication signal among bacterial cells, can accelerate resistance under evolutionary pressure. This study aims to develop a medical dressing to treat PTO by inhibiting QS and regulating the inflammatory microenvironment, which includes severe oxidative stress and acid abscesses, through a reactive oxygen species (ROS)-responsive bond between N1- (4-borobenzoyl)-N3-(4-borobenzoyl)-the N1, the N1, N3, N3-tetramethylpropane-1,3-diamine (TSPBA) and polyvinyl alcohol (PVA), and the amino side chain of hyperbranched polylysine (HBPL). Physically enclosed QS inhibitors subsequently exerted the antibacterial effects. This hydrogel can scavenge hydrogen peroxide (H2O2), superoxide anion free radical (·O2 -), hydroxyl radicals (·OH) and 2,2-di(4-tert-octylphenyl)-1-picryl-hydrazyl (DPPH) to reduce oxidative stress and inhibit "bacteria-to-bacteria communication", thus clearing planktonic bacteria and biofilms, accelerating bacterial plasmolysis, reducing bacterial virulence and interfering with membrane transport. After in vivo treatment with hydrogel, nearly all bacteria are eliminated, inflammation is effectively inhibited, and osteogenesis and bone repair are promoted to facilitate recovery from PTO. The work demonstrates the clinical translational potential of the hydrogel in the treatment of drug-resistant bacteria induced PTO.

Chronic otorrhea and osteomyelitis of the external auditory canal by Achromobacter xylosoxidans: an uncommon diagnosis.

PURPOSE: Achromobacter xylosoxidans is an emerging pathogen mainly associated with resistant nosocomial infections. This bacteria had been isolated in the ear together with other pathogens in cultures from patients with chronic otitis media, but it had never been reported as a cause of osteomyelitis of the external auditory canal. CASE PRESENTATION: We present a unique case of a healthy 81-year-old woman who presented with left chronic otorrhea refractory to topical and oral antibiotic treatment. Otomicroscopy revealed an erythematous and exudative external auditory canal (EAC) with scant otorrhea. The tympanic membrane was intact, but an area of bone remodeling with a small cavity anterior and inferior to the bony tympanic frame was observed. Otic culture isolated multi-drug-resistant A. xylosoxidans, only sensitive to meropenem and cotrimoxazole. Temporal bone computed tomography showed an excavation of the floor of the EAC compatible with osteomyelitis. Targeted antibiotherapy for 12 weeks was conducted, with subsequent resolution of symptoms and no progression of the bone erosion. CONCLUSIONS: Atypical pathogens such as A. xylosoxidans can be the cause of chronic otitis externa. Early diagnosis and specific antibiotherapy can prevent the development of further complications, such as osteomyelitis. In these cases, otic cultures play an essential role to identify the causal germ. This is the first case of EAC osteomyelitis due to A. xylosoxidans reported to date.

Enhanced Chemoradiotherapy for MRSA-Infected Osteomyelitis Using Immunomodulatory Polymer-Reinforced Nanotherapeutics.

The eradication of osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) poses a significant challenge due to its development of biofilm-induced antibiotic resistance and impaired innate immunity, which often leads to frequent surgical failure. Here, the design, synthesis, and performance of X-ray-activated polymer-reinforced nanotherapeutics that modulate the immunological properties of infectious microenvironments to enhance chemoradiotherapy against multidrug-resistant bacterial deep-tissue infections are reported. Upon X-ray radiation, the proposed polymer-reinforced nanotherapeutic generates reactive oxygen species and reactive nitrogen species. To robustly eradicate MRSA biofilms at deep infection sites, these species can specifically bind to MRSA and penetrate biofilms for enhanced chemoradiotherapy treatment. X-ray-activated nanotherapeutics modulate the innate immunity of macrophages to prevent the recurrence of osteomyelitis. The remarkable anti-infection effects of these nanotherapeutics are validated using a rat osteomyelitis model. This study demonstrates the significant potential of a synergistic chemoradiotherapy and immunotherapy method for treating MRSA biofilm-infected osteomyelitis.

Pediatric Multidrug-Resistant Disseminated Tuberculosis Presenting as Small Finger Tuberculous Osteomyelitis: A Case Report.

CASE: We report a case in the United States of a 12-year-old girl with multidrug-resistant tuberculous (MDR-TB) osteomyelitis of the hand managed with surgical debridement and second-line anti-TB therapy. The disease course was complicated by dissemination and multifocal progression. CONCLUSION: Despite early intervention, multidrug resistance makes TB treatment challenging and facilitated progression to disseminated disease in this case. We review the difficulties in diagnosis and treatment of pediatric MDR-TB.