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Azithromycin/vancomycin combination reduced response in CA-MRSA strains
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WASHINGTON — Exposure of both azithromycin-susceptible and azithromycin-resistant community-associated methicillin-resistant Staphylococcus aureus isolates to azithromycin/vancomycin combinations led to a significantly reduced macrophage response to these bacteria, according to results presented here.
While a majority of pediatric patients with infections caused by community-associated methicillin-resistant strains of Staphylococcus aureus (CA-MRSA) are treated with vancomycin, researchers from the Department of Pediatrics at the University of Tennessee Health Science Center had previously reported that combination antimicrobial therapy that includes a macrolide – such as azithromycin – could be superior to monotherapy with cell-wall active antibiotics – such as penicillin or vancomycin.
To evaluate if the addition of azithromycin reduced the macrophage tumor necrosis factor (TNF) response to vancomycin-treated CA-MRSA isolates, regardless of susceptibility to azithromycin, researchers examined three previously characterized CA-MRSA isolates:
- 6U24 which was susceptible to azithromycin (minimum inhibitory concentration 4 mg/L)
- LAC and 7U20, which were resistant to azithromycin (minimum inhibitory concentration more than 256 mg/L)
The researchers exposed RAW 264.7 murine macrophages to live bacteria at concentrations of 10(6)- 10(8) colony-forming units/mL immediately after the addition of vancomycin (20 mg/L) alone or vancomycin in combination with azithromycin (1, 5, or 20 mg/L) to the culture medium.
Alyssa Fesmire
The cells were cultured overnight and the researchers used an enzyme-linked immunosorbent assay (ELISA) to ascertain TNF concentrations in cell supernatants.
According to study results, macrophages stimulated with all three CA-MRSA isolates in the presence of azithromycin secreted significantly less TNF than macrophages in the presence of bacteria exposed to vancomycin alone.
The degree of reduction was considerable for the azithromycin-susceptible 6U24 strain (30 - 74%) and less for the two azithromycin-resistant strains (0 to 67%), yet was statistically significant for each of the three strains with at least one inoculum.
“We found that we were able to use this combination of azithromycin and vancomycin to reduce some of the clinical symptoms of sepsis, especially regarding the treatment of sepsis as far as inflammation goes,” Alyssa Fesmire, a medical student research fellow from the University of Tennessee Health Science Center, told Infectious Diseases in Children. “These findings are clinically relevant as we do not currently use azithromycin to treat CA-MRSA infections, as they have proven resistant. However, the potential benefits of combination antimicrobial therapy of severe CA-MRSA infections require additional study.”
For more information:
Fesmir A. #1533.455. Presented at the Pediatric Academic Societies Annual Meeting; May 4-7, 2013; Washington.
Disclosure: The researchers reports no relevant financial disclosures.
Perspective
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C. Buddy Creech, MD, MPH
This is a fascinating in vitro study that addresses an important clinical question in the treatment of invasive staphylococcal disease: does the mechanism of antimicrobial activity adversely affect the host inflammatory response? Fueled by exposure to live staphylococci, murine macrophages generate significantly less TNF when vancomycin is co-administered with azithromycin, a protein synthesis inhibitor with known anti-inflammatory properties. While azithromycin is not a recommended agent for the treatment of staphylococci, these data should inform our clinical practice patterns when treating patients with staphylococcal sepsis syndromes.
Is it possible that the clinical consequences of staphylococcal sepsis are worsened by rapid bacterial lysis? Could protein synthesis inhibitors (e.g., clindamycin, linezolid, azithromycin) or cell-wall active agents that do not result in rapid bacterial lysis (e.g., daptomycin) reduce the host inflammatory response in such a way as to promote bacteriologic eradication without the inevitable “collateral damage” that we encounter? As we’ve learned time and time again, mice aren’t humans; however, these data deserve our attention, as we consider how to optimize the care of children with life-threatening staphylococcal disease.
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