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Beta-lactam resistance mechanisms of methicillin-resistant Staphylococcus aureus
M Franciolli1, J Bille, M P Glauser
1Department of Internal Medicine, CHUV, Lausanne, Switzerland.
Abstract:
In vitro and in vivo activity of amoxicillin and penicillin G alone or combined with a penicillinase inhibitor (clavulanate) were tested against five isogenic pairs of methicillin-resistant Staphylococcus aureus (MRSA) producing or not producing penicillinase. Loss of the penicillinase plasmid caused an eight times or greater reduction in the MICs of amoxicillin and penicillin G (from greater than or equal to 64 to 8 micrograms/ml), but not of the penicillinase-resistant drugs methicillin and cloxacillin (greater than or equal to 64 micrograms/ml). This difference in antibacterial effectiveness correlated with a more than 10 times greater penicillin-binding protein 2a affinity of amoxicillin and penicillin G than of methicillin and a greater than or equal to 90% successful amoxicillin treatment of experimental endocarditis due to penicillinase-negative MRSA compared with cloxacillin, which was totally ineffective (P less than .001). Amoxicillin was also effective against penicillinase-producing parent MRSA, provided it was combined with clavulanate. Penicillinase-sensitive beta-lactam antibiotics plus penicillinase inhibitors might offer a rational alternative treatment for MRSA infections.
Insights
Amoxicillin and penicillin G are effective against penicillinase-negative MRSA. Combining amoxicillin with clavulanate offers a potential treatment for MRSA infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant public health threat.
- The emergence of antibiotic resistance necessitates novel therapeutic strategies.
- Understanding the mechanisms of resistance is crucial for developing effective treatments.
Purpose of the Study:
- To evaluate the in vitro and in vivo activity of amoxicillin and penicillin G, alone or with clavulanate, against MRSA.
- To investigate the role of penicillinase production in MRSA resistance to beta-lactam antibiotics.
- To assess the potential of penicillinase-sensitive beta-lactams combined with inhibitors as an alternative MRSA treatment.
Main Methods:
- Testing amoxicillin and penicillin G (alone and with clavulanate) against isogenic MRSA pairs (penicillinase-producing vs. non-producing).
- Determining minimum inhibitory concentrations (MICs) and evaluating in vivo efficacy in an experimental endocarditis model.
- Assessing the binding affinity of antibiotics to penicillin-binding protein 2a (PBP2a).
Main Results:
- Loss of penicillinase plasmid reduced amoxicillin and penicillin G MICs by at least eightfold.
- Penicillinase-resistant drugs (methicillin, cloxacillin) showed consistently high MICs (≥64 µg/ml).
- Amoxicillin demonstrated high efficacy in treating experimental endocarditis in penicillinase-negative MRSA models, unlike cloxacillin.
Conclusions:
- Penicillinase production significantly impacts MRSA susceptibility to amoxicillin and penicillin G.
- Amoxicillin combined with clavulanate shows promise for treating MRSA infections, including those with penicillinase production.
- Penicillinase-sensitive beta-lactams plus inhibitors represent a rational therapeutic approach for MRSA infections.