Foreign Body Infection Models to Study Host-Pathogen Response and Antimicrobial Tolerance of Bacterial Biofilm

Nowakowska, Justyna; Landmann, Régine; Khanna, Nina

doi:10.3390/antibiotics3030378

Cited by 38 publications

(46 citation statements)

References 99 publications

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“…Not surprisingly, the Staphylococcal requirements to develop infective endocarditis or a skin abscess, such as specific toxins and superantigens (18, 19), are not the same as those needed for an indwelling catheter infection that can be caused by many types of Staphylococci. Further, a much lower bacterial load (estimated at 10,000-fold lower) is needed to colonize a foreign body than to cause a skin abscess (20). The reason for this is likely the lack of vascularization at the site, and presumably a reduced presence of innate immunity factors (10).…”

Section: Introductionmentioning

confidence: 99%

The Staphylococcal Biofilm: Adhesins, Regulation, and Host Response

2016

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The Staphylococci comprise a diverse genus of Gram-positive, non-motile commensal organisms that inhabit the skin and mucous membranes of humans and other mammals. In general, Staphylococci are benign members of the natural flora, but many species have the capacity to be opportunistic pathogens, mainly infecting individuals who have medical device implants or are otherwise immunocompromised. S. aureus and S. epidermidis are a major source of hospital-acquired infections and are the most common causes of surgical site infections and central line-associated bloodstream infections. The ability of Staphylococci to form biofilms in vivo makes them highly resistant to chemotherapeutics and leads to chronic diseases. These biofilm infections include osteomyelitis, endocarditis, medical device implants, and persistence in the cystic fibrosis lung. Here, we provide a comprehensive analysis of our current understanding of Staphylococcal biofilm formation, with an emphasis on adhesins and regulation, while also addressing how Staphylococcal biofilms interact with the immune system. On the whole, this review will provide a thorough picture of biofilm formation of the Staphylococcus genus and how this mode of growth impacts the host.

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Section: Introductionmentioning

confidence: 99%

The Staphylococcal Biofilm: Adhesins, Regulation, and Host Response

2016

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“…The murine tissue cage infection model, first established in 1982 by Zimmerli et al (30) and modified by Kristian et al (31), has proven to be a suitable tool to study the antiadhesive and anti-infective efficacy of different biomaterial coatings and to assess the pharmacokinetics, efficacy, and cytotoxicity of antimicrobial compounds (22). The model is particularly useful for evaluating the activity of TRL1068, since it distinguishes between planktonic and adherent bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…After healing, bacteria are injected directly into the lumen of the cage, where they form a localized biofilm. In this model, the tissue cage fluid can be aspirated repeatedly without the need to sacrifice the animal (22).…”

Section: Discussionmentioning

confidence: 99%

“…The effect of TRL1068 in disrupting biofilm can be directly observed as a reduction of adherent bacteria. The effect on planktonic bacteria is a secondary effect of the mechanism of action as the released bacteria regain sensitivity to antibiotic treatment (22). The model involves sterile implantation of a perforated Teflon cage subcutaneously in a mouse.…”

Section: Discussionmentioning

confidence: 99%

“…TRL1068 biofilm-disrupting activity on methicillin-resistant S. aureus ATCC 43300 was evaluated using a murine tissue cage infection model as previously described (22,23). The in vivo studies were performed at the University Hospital of Basel, Basel, Switzerland, and were conducted according to the regulations of Swiss veterinary law.…”

Section: Not Done 39mentioning

confidence: 99%

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A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model

Estellés

Woischnig

Liu

et al. 2016

Antimicrob Agents Chemother

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Many serious bacterial infections are difficult to treat due to biofilm formation, which provides physical protection and induces a sessile phenotype refractory to antibiotic treatment compared to the planktonic state. A key structural component of biofilm is extracellular DNA, which is held in place by secreted bacterial proteins from the DNABII family: integration host factor (IHF) and histone-like (HU) proteins. A native human monoclonal antibody, TRL1068, has been discovered using single B-lymphocyte screening technology. It has low-picomolar affinity against DNABII homologs from important Gram-positive and Gram-negative bacterial pathogens. The disruption of established biofilm was observed in vitro at an antibody concentration of 1.2 g/ml over 12 h. The effect of TRL1068 in vivo was evaluated in a murine tissue cage infection model in which a biofilm is formed by infection with methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43300). Treatment of the established biofilm by combination therapy of TRL1068 (15 mg/kg of body weight, intraperitoneal [i.p.] administration) with daptomycin (50 mg/kg, i.p.) significantly reduced adherent bacterial count compared to that after daptomycin treatment alone, accompanied by significant reduction in planktonic bacterial numbers. The quantification of TRL1068 in sample matrices showed substantial penetration of TRL1068 from serum into the cage interior. TRL1068 is a clinical candidate for combination treatment with standard-of-care antibiotics to overcome the drug-refractory state associated with biofilm formation, with potential utility for a broad spectrum of difficult-to-treat bacterial infections.T he understanding of bacterial physiology has fundamentally changed since the discovery of biofilms in the bacterial life cycle (1-3). Biofilms provide an anchor and physical protection for bacterial cells and the physiology and genetic programming of the bacteria shift from the planktonic (free-floating) to a sessile (adherent) state. This shift can result in a substantial reduction of antibiotic sensitivity in the biofilm (4). As much as 65 to 80% of clinically significant bacterial infections resistant to antibiotics are associated with biofilm (5, 6), including those of implants and catheters, infective endocarditis, lung infections associated with cystic fibrosis and chronic obstructive pulmonary disease (COPD), persistent infections of the ears and urinary tract, osteomyelitis, and surgery-associated nosocomial infections. Accordingly, a promising approach to treatment is to disrupt biofilms so that the freed bacteria become sensitive to available antibiotics as well as more fully subject to immune control (7).Biofilms are not simply random assemblies of bacterial and host components. Rather, the polymers in a biofilm form a multinode scaffolding with a semirigid, three-dimensional web-like architecture (8) which serves to exclude host immune cells while allowing the diffusion of nutrients and waste. Comparative genomic studies have identified tens of proteins a...

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Recommendations for design and conduct of preclinical in vivo studies of orthopedic device‐related infection

Moriarty

Harris

Mooney

et al. 2019

Journal Orthopaedic Research

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Orthopedic device-related infection (ODRI), including both fracture-related infection (FRI) and periprosthetic joint infection (PJI), remain among the most challenging complications in orthopedic and musculoskeletal trauma surgery. ODRI has been convincingly shown to delay healing, worsen functional outcome and incur significant socio-economic costs. To address this clinical problem, ever more sophisticated technologies targeting the prevention and/or treatment of ODRI are being developed and tested in vitro and in vivo. Among the most commonly described innovations are antimicrobial-coated orthopedic devices, antimicrobial-loaded bone cements and void fillers, and dual osteo-inductive/antimicrobial biomaterials. Unfortunately, translation of these technologies to the clinic has been limited, at least partially due to the challenging and still evolving regulatory environment for antimicrobial drugdevice combination products, and a lack of clarity in the burden of proof required in preclinical studies. Preclinical in vivo testing (i.e. animal studies) represents a critical phase of the multidisciplinary effort to design, produce and reliably test both safety and efficacy of any new antimicrobial device. Nonetheless, current in vivo testing protocols, procedures, models, and assessments are highly disparate, irregularly conducted and reported, and without standardization and validation. The purpose of the present opinion piece is to discuss best practices in preclinical in vivo testing of antimicrobial interventions targeting ODRI. By sharing these experience-driven views, we aim to aid others in conducting such studies both for fundamental biomedical research, but also for regulatory and clinical evaluation.

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Foreign Body Infection Models to Study Host-Pathogen Response and Antimicrobial Tolerance of Bacterial Biofilm

Cited by 38 publications

References 99 publications

The Staphylococcal Biofilm: Adhesins, Regulation, and Host Response

The Staphylococcal Biofilm: Adhesins, Regulation, and Host Response

A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model

Recommendations for design and conduct of preclinical in vivo studies of orthopedic device‐related infection

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