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[Combination effect between panipenem and vancomycin on highly methicillin-resistant Staphylococcus aureus]
Abstract:
We investigated the in vitro and in vivo combination effects between panipenem (PAPM) and vancomycin (VCM) on highly methicillin-resistant strains of Staphylococcus aureus (MRSA) isolated from various clinical specimens. Examination of combination between panipenem and vancomycin using checkerboard titration showed a good effect with mean fractional inhibitory index of 0.32 +/- 0.12 on 40 MRSA strains, and the effects were judged as synergistic against 33 strains (83%) and additive against 7 strains (17%). In the combination of PAPM and VCM at 1/4 MIC each against exponentially growing MRSA, bactericidal activity was found when PAPM was added at 1 hour or 2 hours prior to VCM-addition, and PAPM with VCM was added simultaneously, although bactericidal activity was scarcely demonstrated when VCM was added at 1 hour or 2 hours prior to PAPM-addition. Bactericidal activity was enhanced against MRSA in the combination of PAPM and VCM at 1/4 MIC each for MRSA than the bactericidal activity of VCM at 1 MIC alone, and the combination showed a strong bactericidal activity against P. aeruginosa. VCM alone, however, had no bactericidal activity in the in vitro mixed cultures of the two bacteria. Furthermore, the combination of PAPM and VCM induced a marked damage to cell surface and bacteriolysis against MRSA and P. aeruginosa in the mixed cultures, although VCM alone induced only slight morphological alterations. Penicillin-binding proteins (PBPs) including MRSA-specific PBP 2' were decreased greatly in the amounts in MRSA-cells with the increase of VCM-treated concentration. The combination therapy of PAPM and VCM showed a greater efficacy than the therapeutic efficacy of each antibiotic alone against mixed infection in burned mice caused by MRSA and P. aeruginosa, and the activity was judged as synergistic based on the FED index smaller than 0.34.
Insights
The combination of panipenem (PAPM) and vancomycin (VCM) shows synergistic and additive effects against methicillin-resistant Staphylococcus aureus (MRSA) in vitro and in vivo. This combination enhances bactericidal activity and reduces bacterial cell surface damage.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat due to its resistance to conventional antibiotics.
- Combination antibiotic therapy is a strategy to overcome antimicrobial resistance and enhance treatment efficacy.
Purpose of the Study:
- To investigate the in vitro and in vivo synergistic effects of panipenem (PAPM) and vancomycin (VCM) against MRSA.
- To evaluate the bactericidal activity and impact on bacterial cell structures of the PAPM-VCM combination.
Main Methods:
- Checkerboard titration was used to assess in vitro synergy between PAPM and VCM against 40 MRSA strains.
- Time-kill assays evaluated bactericidal activity with different addition sequences of PAPM and VCM.
- In vivo efficacy was tested in a mixed infection mouse model involving MRSA and Pseudomonas aeruginosa.
Main Results:
- The PAPM-VCM combination demonstrated synergistic effects against 83% of MRSA strains in vitro.
- The combination exhibited enhanced bactericidal activity compared to VCM alone and induced significant cell surface damage and bacteriolysis.
- In vivo, the combination therapy showed greater efficacy than monotherapy against mixed MRSA and P. aeruginosa infections in burned mice.
Conclusions:
- The combination of panipenem and vancomycin exhibits significant synergistic activity against MRSA, both in vitro and in vivo.
- This combination therapy offers a promising strategy for treating infections caused by resistant MRSA strains.
- The observed synergy may be linked to the disruption of bacterial cell wall synthesis and integrity.