2.1 Introduction
37
linezolid, has shown great promise in its effectiveness (Vjecha et al. 2018; Conradie
et al. 2020) and is proceeding to commercialisation (TB Alliance and Mylan
2019). Another three drug combination of clarithromycin, the proton pump inhibitor
omeprazole, and amoxicillin has been used for the treatment of Helicobacter pylori
but resistance to clarithromycin is now developing making this treatment less effective and extension to a four drug combination now looks a better treatment regime
for Helicobacter pylori as noted in Sect. 2.1.4.1 (Malfertheiner et al. 2011).
It should be noted that every component in a three component mixture does
not have to show antibacterial activity. Illustrative of this, Ferrer-Espada et al.
(2019) have shown that the permeability-increasing antimicrobial peptide polymixin
B nonapeptide can synergize with a MexAB-OprM efflux pump system inhibitor
(particularly with phenylalanine-arginine-naphthylamide, PAβN) when the two are
co-administered with the antibiotic azithromycin in planktonic and biofilm forming
cells of Pseudomonas aeruginosa resulting in a significant boost in potency of the
azithromycin in multi-drug resistant strains of this bacterium. The sensitivity to other
antibiotics could also be changed in this way (Ferrer-Espada et al. 2019).
Administration
There are potential complications in the administration of triple combinations of
drugs in terms of the physical requirement for three separate tablets or in combining
three agents in two tablets one containing two of the drugs and the other just one, or all
three drugs in a single specially constructed tablet or in liposomes or nanoparticles.
There are still a number of considerations though which need to be addressed with
tabletted combinations including the potential for mutual interference with absorption, metabolic clearance or modes of action, together with ensuring there is not
too large a mismatch with dosage schedules of the combination components (Lowe
2018).
After administration, account needs to be taken of pharmacokinetic differences
between the three components. One of the significant potential problems with oral
antibacterial therapies based on drug combinations is, that in vivo, the different drugs
are likely to have different absorption rates and different pharmacokinetic profiles.
This in turn has the potential to compromise antibacterial potency since different
concentrations of drugs could be present at the bacterial target sites at different times.
So ways to maintain efficacious concentrations at each target site can be an issue and
thus incorporating molecular features in each drug to address these issues needs to
be considered. In addition, with triple combinations the likelihood of undesirable
off-target effects is increased.
2.1.3.2 Antibacterial Photodynamic Therapy (aPDT)
A + B + light
This special combination, which forms the basis of photodynamic therapy, is a
variation on type (i) A + B + C triple or more actions but is somewhat different in
37
linezolid, has shown great promise in its effectiveness (Vjecha et al. 2018; Conradie
et al. 2020) and is proceeding to commercialisation (TB Alliance and Mylan
2019). Another three drug combination of clarithromycin, the proton pump inhibitor
omeprazole, and amoxicillin has been used for the treatment of Helicobacter pylori
but resistance to clarithromycin is now developing making this treatment less effective and extension to a four drug combination now looks a better treatment regime
for Helicobacter pylori as noted in Sect. 2.1.4.1 (Malfertheiner et al. 2011).
It should be noted that every component in a three component mixture does
not have to show antibacterial activity. Illustrative of this, Ferrer-Espada et al.
(2019) have shown that the permeability-increasing antimicrobial peptide polymixin
B nonapeptide can synergize with a MexAB-OprM efflux pump system inhibitor
(particularly with phenylalanine-arginine-naphthylamide, PAβN) when the two are
co-administered with the antibiotic azithromycin in planktonic and biofilm forming
cells of Pseudomonas aeruginosa resulting in a significant boost in potency of the
azithromycin in multi-drug resistant strains of this bacterium. The sensitivity to other
antibiotics could also be changed in this way (Ferrer-Espada et al. 2019).
Administration
There are potential complications in the administration of triple combinations of
drugs in terms of the physical requirement for three separate tablets or in combining
three agents in two tablets one containing two of the drugs and the other just one, or all
three drugs in a single specially constructed tablet or in liposomes or nanoparticles.
There are still a number of considerations though which need to be addressed with
tabletted combinations including the potential for mutual interference with absorption, metabolic clearance or modes of action, together with ensuring there is not
too large a mismatch with dosage schedules of the combination components (Lowe
2018).
After administration, account needs to be taken of pharmacokinetic differences
between the three components. One of the significant potential problems with oral
antibacterial therapies based on drug combinations is, that in vivo, the different drugs
are likely to have different absorption rates and different pharmacokinetic profiles.
This in turn has the potential to compromise antibacterial potency since different
concentrations of drugs could be present at the bacterial target sites at different times.
So ways to maintain efficacious concentrations at each target site can be an issue and
thus incorporating molecular features in each drug to address these issues needs to
be considered. In addition, with triple combinations the likelihood of undesirable
off-target effects is increased.
2.1.3.2 Antibacterial Photodynamic Therapy (aPDT)
A + B + light
This special combination, which forms the basis of photodynamic therapy, is a
variation on type (i) A + B + C triple or more actions but is somewhat different in