Intracellular Staphylococcus aureus in bone and joint infections: A mechanism of disease recurrence, inflammation, and bone and cartilage destruction

Alder, Kareme D.; Lee, Inkyu; Munger, Alana M.; Kwon, Hyuk‐Kwon; Morris, Montana T.; Cahill, Sean V.; Back, Jungho; Yu, Kristin E.; Lee, Francis Y.

doi:10.1016/j.bone.2020.115568

Cited by 54 publications

(55 citation statements)

References 171 publications

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“…Key characteristics of osteomyelitis are severe inflammation, vascular impairment, and localized bone loss and destruction (2). The host responds to the presence of bacteria such as S. aureus by releasing inflammatory factors and degradative enzymes from immune cells, which contribute to the destruction of bone matrix and bone trabeculae (1,(5)(6)(7)(8)(9)(10). Many of the innate immune responses involved in antibacterial host defense also have significant impacts on bone homeostasis, and the release of inflammatory mediators at the infection site can result in decreased osteoblast-mediated bone formation and increased osteoclast activation and bone resorption, thereby promoting bone loss.…”

Section: The Development Of Chronic Osteomyelitismentioning

confidence: 99%

Mechanisms of Antibiotic Failure During Staphylococcus aureus Osteomyelitis

Gimza

Cassat

2021

Front. Immunol.

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Staphylococcus aureus is a highly successful Gram-positive pathogen capable of causing both superficial and invasive, life-threatening diseases. Of the invasive disease manifestations, osteomyelitis or infection of bone, is one of the most prevalent, with S. aureus serving as the most common etiologic agent. Treatment of osteomyelitis is arduous, and is made more difficult by the widespread emergence of antimicrobial resistant strains, the capacity of staphylococci to exhibit tolerance to antibiotics despite originating from a genetically susceptible background, and the significant bone remodeling and destruction that accompanies infection. As a result, there is a need for a better understanding of the factors that lead to antibiotic failure in invasive staphylococcal infections such as osteomyelitis. In this review article, we discuss the different non-resistance mechanisms of antibiotic failure in S. aureus. We focus on how bacterial niche and destructive tissue remodeling impact antibiotic efficacy, the significance of biofilm formation in promoting antibiotic tolerance and persister cell formation, metabolically quiescent small colony variants (SCVs), and potential antibiotic-protected reservoirs within the substructure of bone.

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Section: The Development Of Chronic Osteomyelitismentioning

confidence: 99%

Mechanisms of Antibiotic Failure During Staphylococcus aureus Osteomyelitis

Gimza

Cassat

2021

Front. Immunol.

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“…The recent discovery of S. aureus colonization of the osteocyte lacuno canalicular network (OLCN) of live bone via transmission electron microscopy (TEM) analyses of infected bone from mice, and bone biopsies from patients with chronic osteomyelitis, has provided new insights into the problems of antibiotic therapy to treat bone infections [ 16 , 17 , 18 , 19 ]. Specifically, S. aureus within the OLCN is a permanent reservoir of bacteria that cannot be eradicated by host responses or any known treatments short of amputation [ 9 , 20 , 21 , 22 ]. While in vivo bromodeoxyuridine labeling studies in mice have demonstrated that orally administered small molecules have access to S. aureus at the leading edge of the colony within the OLCN [ 17 ], we have also shown that both methicillin-sensitive S. aureus (MSSA) [ 23 ] and methicillin-resistant S. aureus (MRSA) [ 24 ] OLCN invasion cannot be prevented or eradicated by combined high-dose local and systemic antibiotics, likely due to its well-known adaptive responses that are associated with persister cells and small colony variants (SCVs) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid

et al. 2021

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The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “target and release” approach to deliver antibiotics to bone infection sites. A fluorescent bisphosphonate probe was used to demonstrate bone surface labeling adjacent to bacteria in a S. aureus infected mouse tibiae model. Bisphosphonate and hydroxybisphosphonate conjugates of sitafloxacin and tedizolid (BCA) were synthesized using hydroxyphenyl and aminophenyl carbamate linkers, respectively. The conjugates were adequately stable in serum. Their cytolytic activity versus parent drug on MSSA and MRSA static biofilms grown on hydroxyapatite discs was established by scanning electron microscopy. Sitafloxacin O-phenyl carbamate BCA was effective in eradicating static biofilm: no colony formation units (CFU) were recovered following treatment with 800 mg/L of either the bisphosphonate or α-hydroxybisphosphonate conjugated drug (p < 0.001). In contrast, the less labile tedizolid N-phenyl carbamate linked BCA had limited efficacy against MSSA, and MRSA. CFU were recovered from all tedizolid BCA treatments. These results demonstrate the feasibility of BCA eradication of S. aureus biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA.

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“…[23][24][25][26] Intracellular infection and biofilm formation are major mechanisms by which Staphylococcal infections become established (Figure 1). 27,28 Unlike vancomycin, which is typically used to treat MRSA infection, rifampin is effective against biofilms and can target intracellular Staphylococcus. 29,30 Although systemic rifampin is not administered alone out of concern for antibiotic resistance, it has been used as a single-agent local antibiotic for several applications delivered in the form of solutions, powders, and mesh coatings.…”

Section: Introductionmentioning

confidence: 99%

Locally delivered adjuvant biofilm‐penetrating antibiotics rescue impaired endochondral fracture healing caused by MRSA infection

Cahill

Kwon

Back

et al. 2021

Journal Orthopaedic Research

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Infection is a devastating complication following an open fracture. We investigated whether local rifampin-loaded hydrogel can combat infection and improve healing in a murine model of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. A transverse fracture was made at the tibia midshaft of C57BL/6J mice aged 10-12 weeks and stabilized with an intramedullary pin. A total of 1 × 10 6 colony-forming units (CFU) of MRSA was inoculated. A collagen-based hydrogel containing low-dose (60 μg) and high-dose (300 μg) rifampin was applied before closure. Postoperative treatment response was assessed through bacterial CFU counts from tissue and hardware, tibial radiographs and microcomputed tomography (μCT), immunohistochemistry, and histological analyses. All untreated MRSA-infected fractures progressed to nonunion by 28 days with profuse MRSA colonization. Infected fractures demonstrated decreased soft callus formation on safranin O stain compared to controls. Areas of dense interleukin-1β stain were associated with poor callus formation. High-dose rifampin hydrogels reduced the average MRSA load in tissue (p < 0.0001) and implants (p = 0.041). Low-dose rifampin hydrogels reduced tissue bacterial load by 50% (p = 0.021). Among sterile models, 88% achieved union compared to 0% of those infected. Mean radiographic union scale in tibia scores improved from 6 to 8.7 with highdose rifampin hydrogel (p = 0.024) and to 10 with combination local/systemic rifampin therapy (p < 0.0001). μCT demonstrated reactive bone formation in MRSA infection. Histology demonstrated restored fracture healing with bacterial elimination. Rifampinloaded hydrogels suppressed osteomyelitis, prevented implant colonization, and improved healing. Systemic rifampin was more effective at eliminating infection and improving fracture healing. Further investigation into rifampin-loaded hydrogels is required to correlate these findings with clinical efficacy.

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Intracellular Staphylococcus aureus in bone and joint infections: A mechanism of disease recurrence, inflammation, and bone and cartilage destruction

Cited by 54 publications

References 171 publications

Mechanisms of Antibiotic Failure During Staphylococcus aureus Osteomyelitis

Mechanisms of Antibiotic Failure During Staphylococcus aureus Osteomyelitis

Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid

Locally delivered adjuvant biofilm‐penetrating antibiotics rescue impaired endochondral fracture healing caused by MRSA infection

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