Antagonism between Bacteriostatic and Bactericidal Antibiotics Is Prevalent

Abstract

f Combination therapy is rarely used to counter the evolution of resistance in bacterial infections. Expansion of the use of combination therapy requires knowledge of how drugs interact at inhibitory concentrations. More than 50 years ago, it was noted that, if bactericidal drugs are most potent with actively dividing cells, then the inhibition of growth induced by a bacteriostatic drug should result in an overall reduction of efficacy when the drug is used in combination with a bactericidal drug. Our goal here was to investigate this hypothesis systematically. We first constructed time-kill curves using five different antibiotics at clinically relevant concentrations, and we observed antagonism between bactericidal and bacteriostatic drugs. We extended our investigation by performing a screen of pairwise combinations of 21 different antibiotics at subinhibitory concentrations, and we found that strong antagonistic interactions were enriched significantly among combinations of bacteriostatic and bactericidal drugs. Finally, since our hypothesis relies on phenotypic effects produced by different drug classes, we recreated these experiments in a microfluidic device and performed time-lapse microscopy to directly observe and quantify the growth and division of individual cells with controlled antibiotic concentrations. While our single-cell observations supported the antagonism between bacteriostatic and bactericidal drugs, they revealed an unexpected variety of cellular responses to antagonistic drug combinations, suggesting that multiple mechanisms underlie the interactions.

Antibacterial Effect of Ethanolic Extract of Allium sativum on Biofilm Forming Staphylococcus aureus which Cause Folliculitis

“…The antibiotic treatment may select for bacterial strains with physiologically or genetically enhanced capacity to survive high doses of antibiotics. Under certain conditions, it may result in preferential growth of resistant bacteria, while growth of susceptible bacteria is inhibited by the drug (Rhee andGardiner, 2004 andOcampo et al, 2014). In this study the effect of antibiotics on Staphylococcus aureus isolates were tested by using standard disk diffusion method and results were obtained compared with the NCCLs.…”

Enhanced identification of synergistic and antagonistic emergent interactions among three or more drugs

“…Optical density readings at 600 nm (OD 600 ) at 18 h were used to calculate growth rates as compared to the no-drug control at 18 h by taking their ratios at this time point. This procedure has been previously used by us [32] and others [33,34]. Each three-drug experiment was repeated at least three times.…”

In Vitro Activity of Fosfomycin Alone and in Combination with Ceftriaxone or Azithromycin against Clinical Neisseria gonorrhoeae Isolates

“…However, its overall killing effects were slower than those of CRO alone when tested at the same concentrations. This paradoxical phenomenon might be due to the bacteriostatic effect of AZT that inhibits the required exponential growth of gonococcus for the adequate mechanism of action of CRO (37,38). This type of antagonistic effect was not recorded by calculating the FICIs, but it was instead clearly indicated from the killing curves obtained for ATCC 49226 and the clinical N. gonorrhoeae strain AE-7570 of ST1407: the bactericidal action was more rapid for AZT plus CRO at 0.5ϫ the MICs than at 4ϫ the MIC (Fig.…”