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Meropenem-loaded Cement Is Effective in Preventing Gram-negative Osteomyelitis in an Animal Model
Jian Wei1, Siqi Zhou2, Hanwen Gu2
1Department of Joint Orthopedics, Liuzhou People's Hospital, Liuzhou, China.
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 antibiotic-loaded 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.
Results:
The 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 ± 37.9 µg (TOB), 355.6 ± 16.2 µg (MEM), 721.2 ± 40.3 µg (PIP), 477.4 ± 37.1 µg (CAZ), 146.5 ± 11.3 µg (CIP), and 372.1 ± 14.5 µg (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 cement inhibited K. pneumonia growth, and tobramycin cement inhibited P. aeruginosa . Only meropenem demonstrated antimicrobial activity against all gram-negative bacteria on agar diffusion bioassay. Rats treated with meropenem cement showed improved body weight (control: 280.1 ± 4.2 g, MEM: 288.5 ± 6.6 g, mean difference 8.4 [95% CI 4.3 to 12.6]; p < 0.001), improved knee width (control: 13.5 ± 0.3 mm, MEM: 11.8± 0.4 mm, mean difference 1.7 [95% CI 1.4 to 2.0]; p < 0.001), decreased inflammatory marker (control: 316.7 ± 45.0 mm, MEM: 116.5 ± 21.8 mm, mean difference 200.2 [95% CI 162.3 to 238.2]; p < 0.001), decreased radiographic scores (control: 17.7 ± 2.0 mm, MEM: 10.7± 1.3 mm, mean difference 7.0 [95% CI 5.4 to 8.6]; p < 0.001), improved bone volume/total volume (control: 8.7 ± 3.0 mm, MEM: 28.5 ± 5 .5 mm, mean difference 19.8 [95% CI 13.3 to 26.2]; p < 0.001), decreased Rissing scale scores of the knee gross pathology (control: 3.3 ± 0.5, MEM: 1.1 ± 0.7, mean difference 2.2 [95% CI 1.7 to 2.7]; p < 0.001), decreased Petty scale scores of knee synovium (control: 2.9 ± 0.4 mm, MEM: 0.7 ± 0.7 mm, mean difference 2.1 [95% CI 1.7 to 2.5]; p < 0.001), and decreased bacterial counts of the bone and soft tissues and negative bacterial cultures of cement (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively).
Conclusion:
In this current study, MEM cement had the most stable in vitro antimicrobial activities, effective in vivo activity while having acceptable mechanical and elution characteristics, and it may be an effective prophylaxis against skeletal infection caused by gram-negative bacteria.
Clinical Relevance:
Meropenem-loaded acrylic cement is a potentially effective prevention measure for skeletal infection caused by gram-negative bacteria; however, more related clinical research is needed to further evaluate the safety and efficacy.
Insights
Meropenem-loaded acrylic cement demonstrated effective in vitro and in vivo activity against gram-negative bacteria without compromising mechanical properties. This suggests meropenem cement is a promising option for preventing skeletal infections.
Area of Science:
- Orthopedic Surgery
- Infectious Disease
- Biomaterials Science
Background:
- Antibiotic-loaded acrylic cement is standard for preventing skeletal infections post-joint replacement.
- Limited data exists on antibiotic selection for gram-negative bacteria in such applications.
Purpose of the Study:
- Evaluate the mechanical strength, elution, and antimicrobial activity of various antibiotics in acrylic cement.
- Assess the in vivo efficacy of meropenem-loaded cement in a rat model of skeletal infection.
Main Methods:
- In vitro testing of compressive strength, antibiotic elution, and antibacterial properties of tobramycin, meropenem, piperacillin, ceftazidime, ciprofloxacin, and aztreonam in acrylic cement.
- An in vivo study using a rat model with Pseudomonas aeruginosa inoculation to evaluate meropenem-loaded cement compared to unloaded cement.
Main Results:
- All antibiotic cements met ISO 5833 compressive strength standards.
- Meropenem showed sustained antimicrobial activity against four gram-negative bacteria in vitro over 28 days.
- Meropenem-loaded cement significantly improved body weight, reduced inflammation, and decreased bacterial load in the rat model.
Conclusions:
- Meropenem-loaded acrylic cement exhibits stable in vitro antimicrobial activity and effective in vivo performance.
- Meropenem cement possesses acceptable mechanical and elution characteristics, making it a potential prophylactic agent against gram-negative skeletal infections.
