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2 Antibacterial Combinations
2.1.3 Triple Combinations Resulting in Three or More
Actions
Two general types of triple combinations which could result in three or more actions
are considered in this section with examples and suggested extensions. The first type
covers the combination of three separate compounds (A, B, C) each with at least one
action [Type (i)], while the second involves a variation on this approach where one
of the components is a dual acting hybrid (A − B) or related prodrug and the other
two are separate compounds (C, D) with one or more actions [Type (ii)].
2.1.3.1 Type (I) Combination of Three Separate Components A, B
and C
There are a number of examples of the use of combinations of three separate drugs
in antibacterial studies and some selections from these studies include the work of
Beppler et al. (2016), Hamoud et al. (2014), and Tekin et al. (2016), and the review
by Decuyper et al. (2018). Promising outcomes have been reported in terms of effects
on bacterial growth including of problematic strains. Triple antibiotic combinations
were shown to be effective in vitro against extreme drug resistant Pseudomonas
aeruginosa and Acinetobacter baumannii and that the compounds acted synergistically (Aboulmagd and Alsultan 2014). Synergistic interactions have also been noted
with the triple combination of thymol, ethylendiamine tetraacetic acid (EDTA), and
vancomycin, including a significant 16-fold enhancement in sensitivity of the Gramnegative pathogenic bacterium Escherichia coli (Hamoud et al. 2014). The phenolic
monoterpene thymol has antibacterial properties at least in part due to alteration in
membrane permeability and in some outflow of intracellular components subsequent
to disturbance of the plasma membrane lipid fraction (Trombetta et al. 2005). On the
other hand, the glycopeptide antibiotic vancomycin affects cell wall synthesis and
is used for the treatment of Gram-positive bacterial infections. EDTA, a chelating
agent for Ca
2+ and Mg
2+ ions, was included as these ions are important in bacterial
cell wall protection (particularly in Gram-negative bacteria) and it was thought that
if this protection was compromised by chelation then other antibacterials might be
more effective, as was the case.
In other incisive work by Yeh and co-workers (Tekin et al. 2016), the triple drug
combination of ciprofloxacin, clindamycin and streptomycin resulted in an antibacterial synergy against Escherichia coli (decreasing bacterial fitness-growth rates) in
contrast to some other triple antibiotic combinations. Each antibacterial was given at
an individual fixed concentration and the synergistic interaction was in accord with
both the deviation from additivity measure (DA) and the emergent (E3) interaction
algebraic measures. The DA is derived from the two drug framework, while E3 characterises how much of the three-antibacterial interaction is not derived from pairwise
interactions. In the case of the three drug combination there would be three such pairwise situations to be considered. While emergent lethal synergy was seen with the
2 Antibacterial Combinations
2.1.3 Triple Combinations Resulting in Three or More
Actions
Two general types of triple combinations which could result in three or more actions
are considered in this section with examples and suggested extensions. The first type
covers the combination of three separate compounds (A, B, C) each with at least one
action [Type (i)], while the second involves a variation on this approach where one
of the components is a dual acting hybrid (A − B) or related prodrug and the other
two are separate compounds (C, D) with one or more actions [Type (ii)].
2.1.3.1 Type (I) Combination of Three Separate Components A, B
and C
There are a number of examples of the use of combinations of three separate drugs
in antibacterial studies and some selections from these studies include the work of
Beppler et al. (2016), Hamoud et al. (2014), and Tekin et al. (2016), and the review
by Decuyper et al. (2018). Promising outcomes have been reported in terms of effects
on bacterial growth including of problematic strains. Triple antibiotic combinations
were shown to be effective in vitro against extreme drug resistant Pseudomonas
aeruginosa and Acinetobacter baumannii and that the compounds acted synergistically (Aboulmagd and Alsultan 2014). Synergistic interactions have also been noted
with the triple combination of thymol, ethylendiamine tetraacetic acid (EDTA), and
vancomycin, including a significant 16-fold enhancement in sensitivity of the Gramnegative pathogenic bacterium Escherichia coli (Hamoud et al. 2014). The phenolic
monoterpene thymol has antibacterial properties at least in part due to alteration in
membrane permeability and in some outflow of intracellular components subsequent
to disturbance of the plasma membrane lipid fraction (Trombetta et al. 2005). On the
other hand, the glycopeptide antibiotic vancomycin affects cell wall synthesis and
is used for the treatment of Gram-positive bacterial infections. EDTA, a chelating
agent for Ca
2+ and Mg
2+ ions, was included as these ions are important in bacterial
cell wall protection (particularly in Gram-negative bacteria) and it was thought that
if this protection was compromised by chelation then other antibacterials might be
more effective, as was the case.
In other incisive work by Yeh and co-workers (Tekin et al. 2016), the triple drug
combination of ciprofloxacin, clindamycin and streptomycin resulted in an antibacterial synergy against Escherichia coli (decreasing bacterial fitness-growth rates) in
contrast to some other triple antibiotic combinations. Each antibacterial was given at
an individual fixed concentration and the synergistic interaction was in accord with
both the deviation from additivity measure (DA) and the emergent (E3) interaction
algebraic measures. The DA is derived from the two drug framework, while E3 characterises how much of the three-antibacterial interaction is not derived from pairwise
interactions. In the case of the three drug combination there would be three such pairwise situations to be considered. While emergent lethal synergy was seen with the