A positive interaction between inhibitors of protein synthesis and cefepime in the fight against methicillin-resistant Staphylococcus aureus

• Published in: European journal of clinical microbiology & infectious diseases Vol. 32; no. 7; pp. 899 - 907
• Main Authors: Guignard, B., Vouillamoz, J., Giddey, M., Moreillon, P.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-07-2013; Springer; Springer Nature B.V
• Subjects: Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial diseases; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cephalosporins - pharmacology; Drug Synergism; Drugs; Endocarditis; Human bacterial diseases; Infectious diseases; Inhibitors; Internal Medicine; Medical Microbiology; Medical sciences; Microbial Sensitivity Tests; Penicillin; Pharmacology. Drug treatments; Protein synthesis; Protein Synthesis Inhibitors - pharmacology; Proteins; Staphylococcal infections, streptococcal infections, pneumococcal infections; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus infections; Synergism; Switzerland; Linezolid; Minimum Inhibitory Concentration; Cefepime; Tigecycline; Teicoplanin; Microbiology; β-Lactams; Infection; Cephalosporin derivatives; Antibiotic; Protein synthesis; Bacteriosis; Bacteria; Micrococcales; Micrococcaceae; Antibacterial agent; Staphylococcal infection; Staphylococcus aureus
• ISSN: 0934-9723; 1435-4373
• DOI: 10.1007/s10096-013-1824-x

Quinupristin–dalfopristin (Q-D) synergizes with cefepime for the treatment of methicillin-resistant
Staphylococcus aureus
(MRSA). Here, we studied whether the synergism was restricted to MRSA and if it extended to non-beta-lactam cell wall inhibitors or to other inhibitors of protein synthesis. Three MRSA and two methicillin-susceptible
S
.
aureus
(MSSA) strains were tested, including an isogenic pair of
mecA
−
/
mecA
+
S
.
aureus
Newman. The drug interactions were determined by fractional inhibitory concentration (FIC) indices and population analysis profiles. The antibacterial drugs that we used included beta-lactam (cefepime) and non-beta-lactam cell wall inhibitors (D-cycloserine, fosfomycin, vancomycin, teicoplanin), inhibitors of protein synthesis (Q-D, erythromycin, chloramphenicol, tetracycline, linezolid, fusidic acid), and polynucleotide inhibitors (cotrimoxazole, ciprofloxacin). The addition of each protein inhibitor to cefepime was synergistic (FIC ≤ 0.5) or additive (FIC > 0.5 but < 1) against MRSA, but mostly indifferent against MSSA (FIC ≥ 1 but ≤ 4). This segregation was not observed after adding cotrimoxazole or ciprofloxacin to cefepime. Population analysis profiles were performed on plates in the presence of increasing concentrations of the cell wall inhibitors plus 0.25 × minimum inhibitory concentration (MIC) of Q-D. Cefepime combined with Q-D was synergistic against MRSA, but D-cycloserine and glycopeptides were not. Thus, the synergism was specific to beta-lactam antibiotics. Moreover, the synergism was not lost against
fem
mutants, indicating that it acted at another level. The restriction of the beneficial effect to MRSA suggests that the functionality of penicillin-binding protein 2A (PBP2A) was affected, either directly or indirectly. Further studies are necessary in order to provide a mechanism for this positive interaction.