Meropenem-loaded Cement Is Effective in Preventing Gram-negative Osteomyelitis in an Animal Model

Abstract

Background Low-dose antibiotic-loaded acrylic cement is routinely used for preventing skeletal infection or reimplantation in patients with periprosthetic joint infections. However, few reports about the selection of antibiotics in acrylic cement for antigram-negative bacteria have been proposed. Questions/purposes (1) Does the addition of antibiotics (tobramycin, meropenem, piperacillin, ceftazidime, ciprofloxacin, and aztreonam) to acrylic cement adversely affect compressive strength before and after elution? (2) Which antibiotics have the highest cumulative release within 28 days? (3) Which antibiotics showed antimicrobial activity within 28 days? (4) Does meropenem-loaded cement improve body weight, temperature, and other inflammatory markers compared with control unloaded cement? Methods This is an in vitro study that assessed the mechanical strength, antibiotic elution, and antibacterial properties of antibiotic-loaded cement, combined with an animal study in a rat model that evaluated key endpoints from the animal study. In the in vitro study, we added 2 g of tobramycin (TOB), meropenem (MEM), piperacillin (PIP), ceftazidime (CAZ), ciprofloxacin (CIP), and aztreonam (ATM) to 40 g of acrylic cement. The compressive strength, elution, and in vitro antibacterial properties of the antibiotic-loaded cement were detected. Thirty male rats were randomly divided into two groups: CON (antibiotic-unloaded cement) and MEM (meropenem-loaded cement, which had the most stable antibacterial properties of the six tested antibioticloaded cements in vitro within 28 days). The right tibia of all rats underwent arthroplasty and was implanted with the cement, followed by inoculation with Pseudomonas aeruginosa in the knee. General status, serum biomarkers, radiology, microbiological assay, and histopathological tests were assessed over 14 days postoperatively. ResultsThe compressive strength of all tested antibiotic cement combinations exceeded the 70 MPa threshold (the requirement established in ISO 5833). The cumulative release proportions of the raw antibiotic in cement were 1182.8 6 37.9 mg (TOB), 355.6 6 16.2 mg (MEM), 721.2 6 40.3 mg (PIP), 477.4 6 37.1 mg (CAZ), 146.5 6 11.3 mg (CIP), and 372.1 6 14.5 mg (ATM) within 28 days. Over a 28-day period, meropenem cement demonstrated antimicrobial activities against the four tested gram-negative bacteria (Escherichia coli, P. aeruginosa, Klebsiella pneumoniae, and Proteus vulgaris). Ciprofloxacin cement inhibited E. coli growth, ceftazidime and aztreonam Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request. Ethical approval for this study was obtained from...

CORR Insights®: Meropenem-loaded Cement Is Effective in Preventing Gram-negative Osteomyelitis in an Animal Model

“…The work presented by Wei et al [7] is a good study in a string of studies [3] on the hand-mixing of relatively small doses (about 2 grams per 40 grams of acrylic cement) of antibiotic into bone cement to create an antibiotic-loaded cement for fixation in primary arthroplasty. The authors studied meropenem, ceftazidime, piperacillin, ciprofloxacin, aztreonam, and tobramycin for their efficacy against a gram-negative infection in the knee of a rat infected with P. aeruginosa .…”

“…Although this study [7] provided good benchtop data for recipes of particular doses, there is still no accepted or accurate method to determine how much antimicrobial is needed to successfully treat an infection, what concentrations are best, or how those amounts might vary if the wound is inadequately debrided. Future work also needs to evaluate the tradeoffs associated with higher concentrations of antibiotics in the cement; namely, how much mechanical strength is enough for applications in which antibiotic-loaded cement is used?…”

“…This surgical model did not involve the mature biofilms that may be found on an infected implant. The work by Wei et al [7], however, provides clear and useful data that meropenem, ceftazidime, piperacillin, ciprofloxacin, aztreonam, and tobramycin can be used in surgeon-mixed spacers and can be expected to elute into the wound space. These results should give surgeons confidence that any of the antimicrobials studied by Wei et al can be incorporated into hand-mixed spacers and can be expected to elute in accordance with their poragen fraction to combat active infection.…”

“…The answer to the first two questions is likely agent-specific, and it might be wound-specific. That is why work like that of Wei et al [7] represents a good incremental step toward understanding orthopaedic infection. Questions about dose can only be studied in animal models in order to evaluate human outcomes.…”

“…Where Do We Need To Go? Although this study [7] higher concentrations of antibiotics in the cement; namely, how much mechanical strength is enough for applications in which antibiotic-loaded cement is used? Additionally, how much time is needed for the antimicrobial to release from a spacer to sterilize an infected wound?…”