2.1 Introduction
35
triple combination of ciprofloxacin, clindamycin and streptomycin, a significantly
suppressive interaction was observed with erythromycin, cefoxitin and tobramycin.
What is of further interest here from a design perspective is the possible mechanism of action reasons for synergy versus antagonism since this could help refine
the search for new triple combinations and, subsequently, new hybrid or prodrug
designs to counter resistance issues. In the cases noted above ciprofloxacin inhibits
DNA gyrase and topoisomerase IV, cefoxitin inhibits cell wall synthesis, while the
other antibacterials interact mainly either with the 50S (clindamycin; erythromycin)
or 30S (streptomycin; tobramycin) ribosomal sub-units. Also of relevance is that
drug combinations may be more effective at reducing resistance evolution. Yeh and
co-workers have developed (Beppler et al. 2016) a very useful framework to evaluate potentially therapeutically valuable synergies from three-way interactions of
separate antibacterials using Escherichia coli.
While three (and four) drug combination effects are said to arise from the accumulation of pairwise interactions (Wood et al. 2012), this needs to be reassessed
in the light of the work by Yeh’s group, which indicates their re-scaled equations
for three component combinations could be extended to the quantitative analysis of
systems with four components (or higher) and these may give different conclusions.
An emergent four way interaction measure has been derived (Beppler et al. 2016).
Other foreshadowed developments would be to look at the effect of antibacterial
component concentration gradients and timing of addition of each drug on bacterial
growth. The concentration gradient studies could conceivably be extended to quantitatively analyse bacterial growth effects in three component mixtures in which one
component may be a drug efflux inhibitor which would influence the concentration
variation with time of a second and/or third antibacterial component in a mixture
susceptible to such drug efflux. Again this could provide valuable information to
underpin further multi-action antibacterial design approaches.
Triple combination therapy was also advanced to clinical trials with the combination of imipenem, cilastatin and relebactam for the treatment of infections due to
Gram-negative bacteria (Domalaon et al. 2018; Butler et al. 2017). This combination (Recarbrio) has now been approved by the U.S. Food and Drug Administration
for the treatment of particular Gram-negative infections (Papp-Wallace 2019). In this
combination, degradation of the carbapenem antibacterial, imipenem, is mitigated by
the adjuvants cilastatin (a dehydropeptidase I inhibitor) and the β-lactamase inhibitor
relebactam (Fig. 2.12).
Furthermore, cilastatin is a proximal tubule uptake blocker of protonated antibiotics, affording further amelioration of possible kidney damage with this combination. However, some β-lactamases attack imipenem, particularly metallo βlactamases including imipenases (Hong et al. 2015), thus posing a restriction on
the spectrum of use. From this knowledge one might then consider incorporating
another wide spectrum β-lactamase inhibitor in place of relebactam to help advance
this approach. Of particular value in this connection might be the inclusion in the
combination of one of the bicyclic boronates with inhibitory activity against both
serine-β-lactamases and metallo-β-lactamases (Krajnc et al. 2019). A useful recent
35
triple combination of ciprofloxacin, clindamycin and streptomycin, a significantly
suppressive interaction was observed with erythromycin, cefoxitin and tobramycin.
What is of further interest here from a design perspective is the possible mechanism of action reasons for synergy versus antagonism since this could help refine
the search for new triple combinations and, subsequently, new hybrid or prodrug
designs to counter resistance issues. In the cases noted above ciprofloxacin inhibits
DNA gyrase and topoisomerase IV, cefoxitin inhibits cell wall synthesis, while the
other antibacterials interact mainly either with the 50S (clindamycin; erythromycin)
or 30S (streptomycin; tobramycin) ribosomal sub-units. Also of relevance is that
drug combinations may be more effective at reducing resistance evolution. Yeh and
co-workers have developed (Beppler et al. 2016) a very useful framework to evaluate potentially therapeutically valuable synergies from three-way interactions of
separate antibacterials using Escherichia coli.
While three (and four) drug combination effects are said to arise from the accumulation of pairwise interactions (Wood et al. 2012), this needs to be reassessed
in the light of the work by Yeh’s group, which indicates their re-scaled equations
for three component combinations could be extended to the quantitative analysis of
systems with four components (or higher) and these may give different conclusions.
An emergent four way interaction measure has been derived (Beppler et al. 2016).
Other foreshadowed developments would be to look at the effect of antibacterial
component concentration gradients and timing of addition of each drug on bacterial
growth. The concentration gradient studies could conceivably be extended to quantitatively analyse bacterial growth effects in three component mixtures in which one
component may be a drug efflux inhibitor which would influence the concentration
variation with time of a second and/or third antibacterial component in a mixture
susceptible to such drug efflux. Again this could provide valuable information to
underpin further multi-action antibacterial design approaches.
Triple combination therapy was also advanced to clinical trials with the combination of imipenem, cilastatin and relebactam for the treatment of infections due to
Gram-negative bacteria (Domalaon et al. 2018; Butler et al. 2017). This combination (Recarbrio) has now been approved by the U.S. Food and Drug Administration
for the treatment of particular Gram-negative infections (Papp-Wallace 2019). In this
combination, degradation of the carbapenem antibacterial, imipenem, is mitigated by
the adjuvants cilastatin (a dehydropeptidase I inhibitor) and the β-lactamase inhibitor
relebactam (Fig. 2.12).
Furthermore, cilastatin is a proximal tubule uptake blocker of protonated antibiotics, affording further amelioration of possible kidney damage with this combination. However, some β-lactamases attack imipenem, particularly metallo βlactamases including imipenases (Hong et al. 2015), thus posing a restriction on
the spectrum of use. From this knowledge one might then consider incorporating
another wide spectrum β-lactamase inhibitor in place of relebactam to help advance
this approach. Of particular value in this connection might be the inclusion in the
combination of one of the bicyclic boronates with inhibitory activity against both
serine-β-lactamases and metallo-β-lactamases (Krajnc et al. 2019). A useful recent