6. Challenging the antimicrobial lexicon
The term antibiotic – literally ‘opposing life’, derives from
the Greek ἀντι anti , ”against” and βίος bios , ”life”. This
terminology has been extended to antifungal, antiparasitic, and
antiviral drugs, reflecting a lexicon based on Ehrlich’s magic bullet.
Though this lexicon does not accurately reflect the array of
interactions of modern antimicrobials with the host-pathogen
interactome, it has not been problematic. Macrolide antibiotics, for
example, have been used to treat bacterial infections with the knowledge
that their host-modulating properties play a crucial role in pathogen
clearance and disease management. The lexicon is challenged, however,
when 1) antimicrobials of one class exhibit inhibitory or
host-modulating properties characteristic of another class or 2)
antimicrobials are used clinically to treat diseases pertaining to
another pathogen class. The ‘antibiotic’ azithromycin and the
‘antiparasitic agent’ nitazoxanide are examples of antimicrobials that
have done both91-94; azithromycin is clinically used
against malarial parasites and nitazoxanide treats bacterial infections
such as H. pylori 95,96.
Both azithromycin and nitazoxanide are immunomodulatory agents.
Nitazoxanide treatment results in an increase in IFNγ- and
IL-2-secreting CD4+ cells, TLR8-expressing monocytes, IFNα- and IFNβ-
mRNA expression, mRNA specific for type I IFN inducible genes, and mRNA
specific for gene involved in MHC class I
presentation97,98. The antiviral effects of
nitzoxanide and its metabolite derivative tizoxanide result from the
immunomodulatory activity stimulating a strong antiviral immune response
mediated by both native and acquired mechanisms. In over 10 years of
clinical use there has been no reported drug resistance by nitazoxanide
treatment and attempts to produce drug resistance under laboratory
conditions have generally not met with much success99.
The immunomodulatory effects of azithromycin are more well-established,
having been proven beneficial in treating a variety of chronic
illnesses100,101. Azithromycin treatment results in
decreased production of pro-inflammatory cytokines in the acute phase
and promotes resolution of chronic inflammation in the later
phases102. Specifically, azithromycin has direct
activity on airway epithelial cells to maintain their function and
reduce mucus secretion. These characteristics have resulted in the use
of azithromycin in the management of a variety of chronic lung diseases
including chronic obstructive pulmonary disease, cystic fibrosis (CF),
non-CF bronchiectasis, bronchiolitis obliterans syndrome, diffuse
panbronchiolitis, and asthma103. It is conceivable
that the immunomodulatory properties of azithromycin and nitazoxanide
facilitate their treatment of a range of infection types.
With such efficacy against a range of infectious diseases, to define
azithromycin as an antibiotic or nitazoxanide as an antiparasitic agent
oversimplifies their antimicrobial efficacy, precluding discovery of
general infection mechanisms, rapid consideration for pandemics, and
constructive unification of antimicrobial studies. Indeed, in the
present pandemic, several studies addressed this by compiling
pan-pathogen repositioning histories of therapeutic
candidates104. In order to more accurately describe an
antimicrobial candidate’s properties as well as well to hasten their
consideration for pandemics, we highlighted a system used to define
antimicrobials based on both their ability to inhibit a pathogenin vitro and treat the corresponding disease in the clinical
setting105. This system is based on Oprea and
Overington’s Drug Repositioning Evidence Level (DREL) classification
scheme, which assigns a numerical value to the quality of evidence,
which increases as evidence increases from in vitroinvestigations to animal models and human clinical trials (Table
1)106. From this scheme we determined four
antimicrobial types (antibiotics, antifungals, antiparasitics, and
antivirals) can correspond to four DREL numbers for a given
antimicrobial. An antimicrobial that is used clinically as an
antimalarial and an antiviral but has no evidence of efficacy against
bacteria or fungi is a 0:0:4:4 antimicrobial. The order of the DREL
numbers here are: antibiotic = 0, antifungal = 0, antiparasitic = 4,
antiviral = 4. If no investigations have been conducted for an
antimicrobial class for a given therapeutic, an ‘X’ may be used to
denote this.
With an increasing number of repositioning studies being conducted
worldwide, particularly in the midst of the current pandemic, a
concomitant taxonomic structure can not only classify potential general
antimicrobials, but direct future repositioning studies, facilitate
comparative therapeutic investigations, and inform treatment application
in global health emergencies107. From our
classification system based on DREL we determine azithromycin is a
4:0:4:3 antimicrobial (Table 2)108-121. Pan-pathogen
antimicrobials can therefore simply be defined as antimicrobials that
are DREL = 4 for two antimicrobial classes. Previously we propounded the
term ‘broad-spectrum therapeutic’ to denote this; ‘pan-pathogen
antimicrobial’ and ‘broad-spectrum anti-infective’ are preferred
alternatives122.
The system, hereby termed the ‘BFPV’ classification scheme (for
antiBiotic, antiFungal, antiParasitic, antiViral; alternatively:
Bacterial infection, Fungal infection, Parasitic infection, Viral
infection) scores the effectiveness of an antimicrobial for a particular
pathogen type using three major parameters: in vitro activity,in vivo activity, and clinical effectiveness. This represents a
departure from a magic bullet-oriented lexicon by defining an
antimicrobial not solely by its ability to inhibit a pathogen but by its
ability to shift the damage-response curve towards mitigating damage
within the more holistic, physiological context. This classification
would also consider the effectiveness of non-antimicrobial therapeutics
in treating infections, such as dexamethasone for COVID-19. As
pan-pathogen antimicrobial development matures as a discipline in its
own right, the DREL system can be replaced by a more accurate framework
that classifies drugs according to the degree to which they reduce
damage resulting from the host-pathogen interaction as a function of the
host immune response, perhaps based on Casadevall and Pirofski’s ‘Class’
scheme for host-pathogen interactomes20. As with the
damage-response framework, associated classifications and predictions
are subject to further experimental studies to validate or refute the
framework’s ability to account for the perturbation of therapeutic
intervention on the damage-response curve during microbial pathogenesis.