44
2 Antibacterial Combinations
A combination of four drugs, isoniazid, rifampicin, ethambutol and pyrazinamide,
has been used as a standard of care for infections caused by Mycobacterium tuberculosis (Worthington and Melander 2013). Another treatment regime (BPaMZ)
for TB involving four drugs—bedaquiline, pretomanid, moxifloxacin and pyrazinamide—began in November 2014 (Vjecha et al. 2018). This evaluation study has
now progressed to an on-going late-stage SimpliciTB clinical trial for the treatment
of drug-sensitive, and multi drug resistant, TB; very promising results were obtained
with the BPaMZ regimen in an earlier Phase IIb study (TB Alliance and Mylan
2019). But while four or more drugs are used one still needs to show there is a
genuine combination effect of the four (or more).
The pathogen Helicobacter pylori has also been the focus of multi-drug therapy
and one of these was a four drug combination administered as a single capsule with
three compounds plus omeprazole. This treatment regime for Helicobacter pylori
was found to be more effective in eradicating the bacterium compared with the gold
standard triple combination (Malfertheiner et al. 2011). Coming back to one of the
themes in this book, a meta-analysis of randomized clinical trial data has shown that
the antibacterial alkaloid berberine is beneficial in quadruple therapy for Helicobacter
pylori in China, when used in combination with standard triple therapy incorporating
the antibiotics clarithromycin and amoxicillin together with a proton pump inhibitor
as an anti-secretory agent. This then appeared to be a promising protocol to improve
the eradication rate for this bacterium while reducing adverse events and promoting
ulcer healing (Hu et al. 2020).
2.1.4.2 Type (II) Combination (A − B) + C + D + E
This is a variation on the four-component type (i) theme which includes the incorporation of dual or triple action hybrids (A − B) (or related prodrugs) plus three
at least single action drugs thus potentially resulting in more than four interactions or actions. However the author is not aware of any specific realisations of
this antibacterial combination type as yet but it would be of interest to pursue. One
might note that four component systems form the basis of biology and our existence,
namely four different DNA bases rather than say two. Four gives ample opportunity for variety and functional expressions. A similar power could be unleashed
looking at four possible synchronous or near synchronous interactions involving a
number of bacterial targets.This space could be fertile territory for further innovative
developments.
2.1.5 Pentuple Combinations
Five component drug combinations (A + B + C + D + E) were also included in the
work reported by Tekin et al. (2018) in the previous Sect. 2.1.4.1. At a clinical level,
five separate drugs are being used in the TB trial, endTB, which began in December
2 Antibacterial Combinations
A combination of four drugs, isoniazid, rifampicin, ethambutol and pyrazinamide,
has been used as a standard of care for infections caused by Mycobacterium tuberculosis (Worthington and Melander 2013). Another treatment regime (BPaMZ)
for TB involving four drugs—bedaquiline, pretomanid, moxifloxacin and pyrazinamide—began in November 2014 (Vjecha et al. 2018). This evaluation study has
now progressed to an on-going late-stage SimpliciTB clinical trial for the treatment
of drug-sensitive, and multi drug resistant, TB; very promising results were obtained
with the BPaMZ regimen in an earlier Phase IIb study (TB Alliance and Mylan
2019). But while four or more drugs are used one still needs to show there is a
genuine combination effect of the four (or more).
The pathogen Helicobacter pylori has also been the focus of multi-drug therapy
and one of these was a four drug combination administered as a single capsule with
three compounds plus omeprazole. This treatment regime for Helicobacter pylori
was found to be more effective in eradicating the bacterium compared with the gold
standard triple combination (Malfertheiner et al. 2011). Coming back to one of the
themes in this book, a meta-analysis of randomized clinical trial data has shown that
the antibacterial alkaloid berberine is beneficial in quadruple therapy for Helicobacter
pylori in China, when used in combination with standard triple therapy incorporating
the antibiotics clarithromycin and amoxicillin together with a proton pump inhibitor
as an anti-secretory agent. This then appeared to be a promising protocol to improve
the eradication rate for this bacterium while reducing adverse events and promoting
ulcer healing (Hu et al. 2020).
2.1.4.2 Type (II) Combination (A − B) + C + D + E
This is a variation on the four-component type (i) theme which includes the incorporation of dual or triple action hybrids (A − B) (or related prodrugs) plus three
at least single action drugs thus potentially resulting in more than four interactions or actions. However the author is not aware of any specific realisations of
this antibacterial combination type as yet but it would be of interest to pursue. One
might note that four component systems form the basis of biology and our existence,
namely four different DNA bases rather than say two. Four gives ample opportunity for variety and functional expressions. A similar power could be unleashed
looking at four possible synchronous or near synchronous interactions involving a
number of bacterial targets.This space could be fertile territory for further innovative
developments.
2.1.5 Pentuple Combinations
Five component drug combinations (A + B + C + D + E) were also included in the
work reported by Tekin et al. (2018) in the previous Sect. 2.1.4.1. At a clinical level,
five separate drugs are being used in the TB trial, endTB, which began in December