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.