A New Antibiotic-Loaded Sol-Gel Can Prevent Bacterial Prosthetic Joint Infection: From in vitro Studies to an in vivo Model

Aims Current treatments of prosthetic joint infection (PJI) are minimally effective against Staphylococcus aureus biofilm. A murine PJI model of debridement, antibiotics, and implant retention (DAIR) was used to test the hypothesis that PlySs2, a bacteriophage-derived lysin, can target S. aureus biofilm and address the unique challenges presented in this periprosthetic environment. Methods The ability of PlySs2 and vancomycin to kill biofilm and colony-forming units (CFUs) on orthopaedic implants were compared using in vitro models. An in vivo murine PJI model of DAIR was used to assess the efficacy of a combination of PlySs2 and vancomycin on periprosthetic bacterial load. Results PlySs2 treatment reduced 99% more CFUs and 75% more biofilm compared with vancomycin in vitro. A combination of PlySs2 and vancomycin in vivo reduced the number of CFUs on the surface of implants by 92% and in the periprosthetic tissue by 88%. Conclusion PlySs2 lysin was able to reduce biofilm, target planktonic bacteria, and work synergistically with vancomycin in our in vitro models. A combination of PlySs2 and vancomycin also reduced bacterial load in periprosthetic tissue and on the surface of implants in a murine model of DAIR treatment for established PJI. Cite this article: Bone Joint J 2020;102-B(7 Supple B):3–10.

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Successful Clinical Use of Daptomycin-Impregnated Bone Cement in Two-Stage Revision Hip Surgery for Prosthetic Joint Infection

Annals of Pharmacotherapy ◽

10.1345/aph.1r486 ◽

2013 ◽

Vol 47 (1) ◽

pp. e2-e2 ◽

Cited By ~ 13

Author(s):

Nicholas J Cortes ◽

John M Lloyd ◽

Leszek Koziol ◽

Lawrence O'Hara

Keyword(s):

Bone Cement ◽

Prosthetic Joint Infection ◽

Revision Surgery ◽

Past History ◽

Joint Infection ◽

Pmma Bone Cement ◽

Prosthetic Joint ◽

History Of

OBJECTIVE To describe the safe and successful use of daptomycin-impregnated polymethyl methacrylate (PMMA) bone cement in the treatment of a case of recurrent prosthetic joint infection in a patient with multiple antibiotic allergies and past colonization with multiply antibiotic-resistant organisms. CASE SUMMARY A 79-year-old female had a history of chronic recurrent left prosthetic hip infection. The patient had confirmed allergies to multiple antibiotics and a past history of colonization with methicillin-resistant Staphylococcus aureus. At first-stage revision surgery, the infected prosthesis was removed and samples were sent for microbiologic culture. A spacer device was fashioned, with incorporation of daptomycin and gentamicin into the PMMA bone cement at a concentration of 5% w/w for each antibiotic. Systemic daptomycin and gentamicin were administered postoperatively for 14 days. Propionibacterium acnes was isolated from deep-tissue specimens. The patient made excellent postoperative progress and was discharged after 2 weeks. Second-stage revision surgery was performed at 6 months, with no signs of persistent infection. She remained well, pain free, and mobilizing independently 2 years later. DISCUSSION Daptomycin, a cyclic lipopeptide antibiotic, is approved for systemic treatment of endocarditis and skin and soft tissue infections. In vitro data demonstrate acceptable drug elution from and tensile strength of daptomycin-impregnated PMMA bone cement; however, clinical data are lacking. In our patient's case, the cement formulation was well tolerated, with no adverse effects detected, and demonstrated adequate mechanical strength in vivo. Infection with P. acnes, an unusual pathogen, was successfully treated. Further clinical studies are required to assess the efficacy of daptomycin-impregnated cement in infection with more typical pathogens, such as S. aureus. CONCLUSIONS Daptomycin impregnation of PMMA bone cement may be an option in cases in which patient or pathogen factors preclude use of routinely incorporated agents.

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Ceftaroline-Fosamil Efficacy against Methicillin-Resistant Staphylococcus aureus in a Rabbit Prosthetic Joint Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03600-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6496-6500 ◽

Cited By ~ 13

Author(s):

Laure Gatin ◽

Azzam Saleh-Mghir ◽

Jason Tasse ◽

Idir Ghout ◽

Frédéric Laurent ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Prosthetic Joint Infection ◽

Joint Infection ◽

Infection Model ◽

Ceftaroline Fosamil ◽

Methicillin Resistant ◽

Prosthetic Joint ◽

Intramedullary Canal

ABSTRACTCeftaroline (CPT), the active metabolite of the prodrug ceftaroline-fosamil (CPT-F), demonstratesin vitrobactericidal activity against methicillin-resistantStaphylococcus aureus(MRSA) and is effective in rabbit models of difficult-to-treat MRSA endocarditis and acute osteomyelitis. However, itsin vivoefficacy in a prosthetic joint infection (PJI) model is unknown. Using a MRSA-infected knee PJI model in rabbits, the efficacies of CPT-F or vancomycin (VAN) alone and combined with rifampin (RIF) were compared. After each partial knee replacement with a silicone implant that fit into the tibial intramedullary canal was performed, 5 × 107MRSA CFU (MICs of 0.38, 0.006, and 1 mg/liter for CPT, RIF, and VAN, respectively) was injected into the knee. Infected animals were randomly assigned to receive no treatment (controls) or CPT-F (60 mg/kg of body weight intramuscularly [i.m.]), VAN (60 mg/kg i.m.), CPT-F plus RIF (10 mg/kg i.m.), or VAN plus RIF starting 7 days postinoculation and lasting for 7 days. Surviving bacteria in crushed tibias were counted 3 days after ending treatment. Although thein vivomean log10CFU/g of CPT-treated (3.0 ± 0.9,n= 12) and VAN-treated (3.5 ± 1.1,n= 12) crushed bones was significantly lower than those of controls (5.6 ± 1.1,n= 14) (P< 0.001), neither treatment fully sterilized the bones (3/12 were sterile with each treatment). The mean log10CFU/g values for the antibiotics in combination with RIF were 1.9 ± 0.5 (12/14 were sterile) for CPT-F and 1.9 ± 0.5 (12/14 were sterile) for VAN. In this MRSA PJI model, the efficacies of CPT-F and VAN did not differ; thus, CPT appears to be a promising antimicrobial agent for the treatment of MRSA PJIs.

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A New Antifungal-Loaded Sol-Gel Can Prevent Candida albicans Prosthetic Joint Infection

Antibiotics ◽

10.3390/antibiotics10060711 ◽

2021 ◽

Vol 10 (6) ◽

pp. 711

Author(s):

Hugo Garlito-Díaz ◽

Jaime Esteban ◽

Aranzazu Mediero ◽

Rafael Alfredo Carias-Cálix ◽

Beatriz Toirac ◽

...

Keyword(s):

Candida Albicans ◽

Bone Mineral ◽

Prosthetic Joint Infection ◽

New Technology ◽

Joint Infection ◽

Sol Gel ◽

Positive Culture ◽

Mineral Density ◽

Prosthetic Joint

Fungal PJI is one of the most feared complications after arthroplasty. Although a rare finding, its high associated morbidity and mortality makes it an important object of study. The most frequent species causing fungal PJI is C. albicans. New technology to treat this type of PJI involves organic–inorganic sol-gels loaded with antifungals, as proposed in this study, in which anidulafungin is associated with organophosphates. This study aimed to evaluate the efficacy of an anidulafungin-loaded organic–inorganic sol-gel in preventing prosthetic joint infection (PJI), caused by Candida albicans using an in vivo murine model that evaluates many different variables. Fifty percent (3/6) of mice in the C. albicans-infected, non-coated, chemical-polished (CP)-implant group had positive culture and 100% of the animals in the C. albicans-infected, anidulafungin-loaded, sol-gel coated (CP+A)-implant group had a negative culture (0/6) (p = 0.023). Taking the microbiology and pathology results into account, 54.5% (6/11) of C. albicans-infected CP-implant mice were diagnosed with a PJI, whilst only 9.1% (1/11) of C. albicans-infected CP+A-implant mice were PJI-positive (p = 0.011). No differences were observed between the bone mineral content and bone mineral density of noninfected CP and noninfected CP+A (p = 0.835, and p = 0.181, respectively). No histological or histochemical differences were found in the tissue area occupied by the implant among CP and CP+A. Only 2 of the 6 behavioural variables evaluated exhibited changes during the study: limping and piloerection. In conclusion, the anidulafungin-loaded sol-gel coating showed an excellent antifungal response in vivo and can prevent PJI due to C. albicans in this experimental model.

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Adjunctive Rifampin Is Crucial to Optimizing Daptomycin Efficacy against Rabbit Prosthetic Joint Infection Due to Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00675-11 ◽

2011 ◽

Vol 55 (10) ◽

pp. 4589-4593 ◽

Cited By ~ 66

Author(s):

Azzam Saleh-Mghir ◽

Claudette Muller-Serieys ◽

Aurélien Dinh ◽

Laurent Massias ◽

Anne-Claude Crémieux

Keyword(s):

Staphylococcus Aureus ◽

Prosthetic Joint Infection ◽

Joint Infection ◽

Detection Threshold ◽

High Dose ◽

Prosthesis Infection ◽

Methicillin Resistant ◽

Prosthetic Joint ◽

Mutant Strains

ABSTRACTDaptomycin is an attractive option for treating prosthetic joint infection, but the 6-mg/kg of body weight/day dose was linked to clinical failure and emergence of resistance. Using a methicillin-resistantStaphylococcus aureus(MRSA) knee prosthesis infection in rabbits, we studied the efficacies of high-dose daptomycin (22 mg/kg given intravenously [i.v.] once daily [o.d.]; equivalent to 8 mg/kg/day in humans) or vancomycin (60 mg/kg given intramuscularly [i.m.] twice daily [b.i.d.]), both either alone or with adjunctive rifampin (10 mg/kg i.m. b.i.d.). After partial knee replacement with a silicone implant, 107MRSA CFU was injected into the knees. Treatment started 7 days postinoculation and lasted 7 days. Positive cultures were screened for the emergence of mutant strains, defined as having 3-fold-increased MICs. Althoughin vivomean log10CFU/g of daptomycin-treated (4.23 ± 1.44;n= 12) or vancomycin-treated (4.63 ± 1.08;n= 12) crushed bone was significantly lower than that of controls (5.93 ± 1.15;n= 9) (P< 0.01), neither treatment sterilized bone (2/12 and 0/12 rabbits with sterile bone, respectively). Daptomycin mutant strains were found in 6/12, 3/12, and 2/9 daptomycin-treated, vancomycin-treated, and control rabbits, respectively; no resistant strains emerged (MIC was always <1 mg/liter). Adjunctive rifampin with daptomycin (1.47 ± 0.04 CFU/g of bone [detection threshold]; 11/11 sterile bones) or vancomycin (1.5 ± 0.12 CFU/g of bone; 6/8 sterile bones) was significantly more effective than monotherapy (P< 0.01) and prevented the emergence of daptomycin mutant strains. In this MRSA joint prosthesis infection model, combining rifampin with daptomycin was highly effective. Daptomycin mutant strains were isolatedin vivoeven without treatment, but adjunctive rifampin prevented this phenomenon, previously found after monotherapy in humans.

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691. Activity of TNP-2092 Against Biofilms Formed by Prosthetic Joint Infection-Associated Staphylococci

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.759 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S313-S313 ◽

Cited By ~ 1

Author(s):

Cody Fisher ◽

Suzannah Schmidt-Malan ◽

Ying Yuan ◽

Shijie He ◽

Zhenkun Ma ◽

...

Keyword(s):

Prosthetic Joint Infection ◽

Joint Infection ◽

Drug Binding ◽

Vitro Activity ◽

Logarithmic Phase ◽

Investigational Drug ◽

In Vitro Activity ◽

Material Support ◽

Prosthetic Joint

Abstract Background Infection occurs in ~1–2% of prosthetic joint replacement surgeries, with staphylococci being the most common cause. TNP-2092 is an investigational drug composed of rifamycin and quinolizinone pharmacophores conjugated via a stable linker. Here, we determined TNP-2092’s in vitro activity against biofilms formed by staphylococci associated with prosthetic joint infection and compared activity to that of ciprofloxacin and rifampin alone and in combination, as well as to daptomycin and vancomycin. Methods A total of 80 staphylococcal isolates (40 Staphylococcus aureus and 40 Staphylococcus epidermidis) were studied. Planktonic state minimum inhibitory concentrations (MICs) of TNP-2092, ciprofloxacin, rifampin, ciprofloxacin + fixed concentration (1 mg/mL) rifampin, daptomycin and vancomycin were determined following CLSI guidelines. Tween-80（0.002%）was added to TNP-2092 to prevent drug binding to plastic plates. Minimum biofilm inhibitory concentrations (MBICs) and minimum biofilm bactericidal concentration (MBBCs) were determined as follows. Bacteria were grown in TSB to logarithmic phase and adjusted to a turbidity of 0.5 McFarland; 150 µL aliquots were transferred to individual wells of 96-well flat-bottom plates and the plates covered with 96-pegged lids. Plates were incubated on a shaker for 5 hours at 37℃. Pegged lids were rinsed using 200 µL PBS/well and placed into a microtiter plate containing serial 2-fold drug dilutions in CAMHB Plates were incubated for 20–24 hours at 37°C and MBICs read by visual turbidity. Pegged lids were rinsed with PBS and placed into plates filled with 200 µL CAMHB/well and incubated for 20–24 hours at 37°C after which MBBCs were determined by assessing visual turbidity. Results Results shown in the table. Conclusion TNP-2092 has promising in vitro activity against prosthetic joint infection-associated staphylococcal biofilms. Disclosures Robin Patel, MD, ASM and IDSA: Other Financial or Material Support, Travel reimbursement, editor’s stipends; CD Diagnostics, Merck, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, ContraFect, TenNor Therapeutics Limited, Shionogi: Grant/Research Support; Curetis, Specific Technologies, NextGen Diagnostics, PathoQuest, Qvella: Consultant; NBME, Up-to-Date, the Infectious Diseases Board Review Course: Honorarium recipient, Other Financial or Material Support; Patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued: Other Financial or Material Support, Patents.

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In vitro activity of oritavancin in combination with rifampin or gentamicin against prosthetic joint infection-associated methicillin-resistant Staphylococcus epidermidis biofilms

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2018.07.012 ◽

2018 ◽

Vol 52 (5) ◽

pp. 608-615 ◽

Cited By ~ 2

Author(s):

Qun Yan ◽

Melissa J. Karau ◽

Yash S. Raval ◽

Robin Patel

Keyword(s):

Prosthetic Joint Infection ◽

Staphylococcus Epidermidis ◽

Joint Infection ◽

Vitro Activity ◽

In Vitro Activity ◽

Methicillin Resistant ◽

Prosthetic Joint

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In Vitro and In Vivo Evaluation of Vancomycin-Loaded PMMA Cement in Combination with Ultrasound and Microbubbles-Mediated Ultrasound

BioMed Research International ◽

10.1155/2015/309739 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 8

Author(s):

Tiao Lin ◽

Xun-Zi Cai ◽

Ming-Min Shi ◽

Zhi-Min Ying ◽

Bin Hu ◽

...

Keyword(s):

Bone Cement ◽

Joint Infection ◽

Study Groups ◽

In Vivo Evaluation ◽

Pmma Bone Cement ◽

Prosthetic Joint ◽

New Zealand White Rabbits ◽

Pmma Cement

Ultrasound (US) has been used to increase elution of antibiotic from an antibiotic-loaded poly(methyl methacrylate) (PMMA) bone cement (ALBC). We aimed to further investigate whether microbubbles-mediated US (US + MB) facilitate elution of vancomycin (VAN) from cylindrical specimens and enhance the activity of the eluted antibiotic againstStaphylococcus aureus(S. aureus) in vitro. The study groups comprised cylindrical bone cement fabricated with VAN (VAN), ALBC using US (VAN + US), and ALBC using MB-mediated US (VAN + US + MB). We also carried out an in vivo study involving the activity of VAN from cylindrical cement implanted in tibiae of New Zealand white rabbits inoculated withS. aureus. We found that (1) in vitro, elution from VAN + US + MB cylinders was significantly higher than from either the VAN or VAN + US specimens; (2) the activity of the eluted VAN from the VAN + US + MB cylinders against planktonicS. aureuswas significantly higher than from either the control or VAN or VAN + US specimens; and (3) in the rabbits, the activity of the eluted VAN from the VAN + US + MB cylinders againstS. aureuswas significantly higher than from either the control or VAN or VAN + US specimens. The present results suggest that VAN-loaded PMMA cement irradiated with MB-mediated US may have a role in controlling prosthetic joint infection.

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Plectasin Shows Intracellular Activity against Staphylococcus aureus in Human THP-1 Monocytes and in a Mouse Peritonitis Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00685-09 ◽

2009 ◽

Vol 53 (11) ◽

pp. 4801-4808 ◽

Cited By ~ 33

Author(s):

Karoline Sidelmann Brinch ◽

Anne Sandberg ◽

Pierre Baudoux ◽

Françoise Van Bambeke ◽

Paul M. Tulkens ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Animal Studies ◽

Kinetic Studies ◽

Response To Therapy ◽

In Vitro Studies ◽

In Vivo Model ◽

Intracellular Activity ◽

Peritonitis Model

ABSTRACT Antimicrobial therapy of infections with Staphylococcus aureus can pose a challenge due to slow response to therapy and recurrence of infection. These treatment difficulties can partly be explained by intracellular survival of staphylococci, which is why the intracellular activity of antistaphylococcal compounds has received increased attention within recent years. The intracellular activity of plectasin, an antimicrobial peptide, against S. aureus was determined both in vitro and in vivo. In vitro studies using THP-1 monocytes showed that some intracellular antibacterial activity of plectasin was maintained (maximal relative efficacy [E max], 1.0- to 1.3-log reduction in CFU) even though efficacy was inferior to that of extracellular killing (E max, >4.5-log CFU reduction). Animal studies included a novel use of the mouse peritonitis model, exploiting extra- and intracellular differentiation assays, and assessment of the correlations between activity and pharmacokinetic (PK) parameters. The intracellular activity of plectasin was in accordance with the in vitro studies, with an E max of a 1.1-log CFU reduction. The parameter most important for activity was fC peak/MIC, where fC peak is the free peak concentration. These findings stress the importance of performing studies of extra- and intracellular activity since these features cannot be predicted from traditional MIC and killing kinetic studies. Application of both the THP-1 and the mouse peritonitis models showed that the in vitro results were similar to findings in the in vivo model with respect to demonstration of intracellular activity. Therefore the in vitro model was a good screening model for intracellular activity. However, animal models should be applied if further information on activity, PK/pharmacodynamic parameters, and optimal dosing regimens is required.

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