Table 1.

Strengths and weaknesses (internal factors), opportunities and threats (external factors) of each class of treatment in clinical development against P. aeruginosa.

Type	Strengths	Weaknesses	Opportunities	Threats
Vaccines	- Prophylactic strategy with a response in early stage of infection - Multitargeting possible/specificity - Reduced probability of resistance - Well define target population (high risks patients for opportunistic infection to improve immunity)	- Non-immediate action - Limited predictive value of animal models (immune system complexity) - Weak preclinical pipeline - No vaccine currently in clinical trial - Immunization dependent of the patient immune system status	- COVID-19 vaccine development change of paradigm - New technologies (reverse vaccinology, adjuvants optimization, mRNA) - Spread of MDR as a reason to consider vaccination	- Image of low morbidity/mortality of P. aeruginosa infection in general population - Burden of disease and incidence rate not well define in high-risk patients - Development mostly in health-care associated pneumonia - Difficulties to generate robust data to support approval (how to design clinical trial regarding complexity of infections) - Non-inferiority clinical trial (design strategy with lack of distinct benefit over existing treatment) - Non-MDR arm used in the studies design; difficulties to recruit patients with MDR - Duration of clinical trial in the current development paradigm - High-risk strategies for innovative treatment (new targets or new type of drug; high attrition rate of phase I) - Cost of diagnosis before use of drugs with narrow spectrum - Cost of biotherapies manufacturing versus traditional drugs - Strong dependence on public and/or philanthropic funding - High need of innovation not or partially covered - Lack of commercial interest in developing new antibacterial drugs (high risk development, low return on investment expected, new drugs will be used as last resort) - Low economic value of novel antibiotic versus innovative treatment of chronical diseases - Many big pharmaceuticals companies abandoned R&D programs - Challenge of clinical development by biotechnologies companies
Antibodies	- Immediate protection (preventive or adjunctive therapy possible) - Immunization independent of the patient immune system status - Multitargeting possible/specificity - Anti-virulence factors strategy with probability of reduced resistance - Narrow spectrum avoiding the disruption of microbiota	- Mostly intravenous administration not ideal for immunocompromised patients - Large proteins - Usually narrow spectrum of activity necessitating diagnosis before to treat (specialized and costly health-care facilities)	- mAb technology well known in cancer or autoimmune diseases treatment - Manufacturing methods and safety profile well established - DNA mAb to overcome cost
Polymyxins	- Broad-spectrum activity - Potentiate and extend the spectrum of conventional antibiotics (synergy) - Efficacy against both quiescent and growing bacteria	- Emergence of resistance - Large spectrum of activity engendering dysbiose - Possible toxicity against host - Currently last line of defense	- No newer alternatives: the urgent need to optimize their clinical use - Substantial progress made in understanding complexity of polymyxins and “soft drug design”
New antibiotics (new MoA)	- New mode of action less susceptible to induce resistance - Broad or narrow activity spectrum	- Based on low evidence, clinicians appear reluctant to use new antibiotic agents - Safety profile less known	- Substantial knowledge of rich ecological niches that produces antibiotics as secondary metabolite - Human microbiota research enthusiasm
New combinations of β-lactam/β-lactamase inhibitor	- Synergic effect, restoring activity of β-lactam - Counteract β-lactamase defense strategy	- Resistance mechanisms beyond the production of β-lactamases - Broad-spectrum of antibiotic resistance/cross resistance - Short-term option	- Highly developed antibacterial β-lactam based clinical pipeline.
Phages	- Self amplification at infection site - Biofilm penetration (possible lysis) - Specificity of action avoiding microbiome disruption - Escape mutants could be less pathogenic due to loss of surface factors expression	- Lack of knowledge about phage mode of action - Strong selective pressure to develop resistance - Diagnosis necessary for personalized therapy - Immunogenicity of phage	- Availability for patients in Eastern Europe specialized centers - Compassionate use as clinical experience - Cost effective - Human microbiome research (including largely phagome)
Iron metabolism disruption	- Activity against Gram-negative and Gram-positive (broad spectrum of activity)	- Production of high level of siderophore pyoverdine to compensate - Lack of knowledge about exact mode of action	- Untapped potential of metal-based antibiotics versus organics compounds
Anti-biofilm	- Sensibilize bacteria to antibiotic - Strategy with reduced probability of resistance - Can supplement antibiotics for increase efficacy - Specificity of action avoiding microbiota depletion	- Requires a combination therapy - Effective in strain infection with mucoid phenotype	- Substantial knowledge of virulence mechanisms of pathogen bacteria - Biofilm well recognized as a threat in healthcare institutions
Other anti-virulence factors	- Strategy with reduced probability of resistance or selection of less virulent strains - Specificity of action avoiding microbiota depletion	- Diagnosis necessary for personalized therapy - Plasticity of virulence factors expression - Require a combination therapy	- The rise of anti-virulence strategy (large number of putative virulence targets) - Anti-virulence drugs already approved (exotoxins blockage)

This table is based on the following references for vaccines (Merakou et al., 2018; Bianconi et al., 2019; Theuretzbacher et al., 2020; Sainz-Mejías et al., 2020; Micoli et al., 2021; Antonelli et al., 2021), antibodies (Lakemeyer et al., 2018; Theuretzbacher et al., 2020; Adlbrecht et al., 2020; Yaeger et al., 2021; Zurawski and McLendon, 2020), polymyxins (Li, et al., 2019; Theuretzbacher et al., 2020; Lepak et al., 2020), new antibiotics (WHO, 2021; Dickey et al., 2017; Tse et al., 2017), new combinations of β-lactam/β-lactamase inhibitor (WHO, 2021; Theuretzbacher et al., 2020), phages (Friman et al., 2016; Jault et al., 2019; Patil et al., 2021), iron metabolism disruption (Zhang et al., 2021; Frei et al., 2020), anti-biofilm (Dickey et al., 2017), and other anti-virulence factors (Dickey et al., 2017; Theuretzbacher et al., 2020).