Understanding resistance in Pseudomonas

Pseudomonas aeruginosa (PA) is the most common multi-drug resistance (MDR) pathogen in hospitalized patients, increases duration of hospitalization, and, despite the appropriate treatment, has an attributable mortality of 13.5% [1]. Risk factors for PA acquisition in the ICU are advanced age, length of mechanical ventilation, previous antibiotic exposure, transfer from a medical unit or ICU, and admission to a ward with high incidence [2]. PA can develop an MDR phenotype through a complex genome including several intrinsic and acquired mechanisms to several antibiotics depicted in Supplementary Fig. 1 [3–5]. It is widely believed that acquiring several resistance elements by PA and other pathogenic bacteria may lead a negative fitness and a less virulent pathogen. However, this concept has been challenged recently, indicating that resistance genes may provide a survival advantage with increased in vivo fitness [6]. In turn, this may have serious implications in the clinical setting that virulent strains with MDR phenotypes may settle as the primary pathogens in infected, high-risk patients. Fever/hypothermia, PIRO score > 2, vasopressors at infection onset, and recent antipseudomonal cephalosporin exposure have been found to be independent predictors of MDR-PA infections [7, 8].

The arsenal of antibiotics against MDR/XDR P. aeruginosa is awaiting promising molecules (Supplementary Table 1) [5, 9–11]. Two molecules in late-stage of development are quite promising in the treatment of XDR P. aeruginosa, because they retain activity in the presence of metallo-enzymes; cefiderocol and cefepime–zidebactam due to their extended spectrum, encompassing all current mechanisms of resistance in MDR and XDR P. aeruginosa [5, 9, 10]. Although results from clinical trials are pending, murepavadin holds promise in the treatment of XDR strains (it was used as single antipseudomonal agent or combined with a standard antipseudomonal antibiotic). However, early in vitro reports revealed mutations indicative of a resistance mechanism shared with colistin, indicating that pre-existing colistin resistance involving lipopolysaccharide modifications could impede activity of murepavadin.

Alternatives to antimicrobial strategies, include new delivery methods (nebulization and encapsulation of antibiotics), vaccines—monoclonal antibodies (MA), and modulation of patient’s immune response. Nebulization of antibiotics (mostly of colistin and aminoglycosides) has been used in heterogeneous dosage regimens and indications, ranging from ventilation-associated pneumonia (VAP) and ventilator-associated tracheobronchitis (VAT) to colonization by resistant P. aeruginosa strains. Their use is hampered by the lack of standardization and broad experience [12]. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests the administration of antibiotics by aerosolisation in mechanically ventilated adults as a practice restricted to salvage therapy in VAP by difficult-to-treat organisms under a strict protocol of administration [13]. New delivery methods such as encapsulation of antibiotics in nanocarriers improve the drug diffusion, protect the drug from undesired degradation, control drug release, and increase uptake in the infected site [14]. These methods use anionic liposomes (with positive results in a model of pneumonia caused by P. aeruginosa in the absence of any additional antibiotic treatment), polyacid nanoparticles, water-soluble oligosaccharide conjugates, polymeric nanocomposites, or solid lipid nanoparticles. Ciprofloxacin, meropenem, and aminoglycosides have already been encapsulated into liposomes or loaded into nanoparticles [14].

Therapeutic approaches through modulation of patient’s response or the pathogenicity of P. aeruginosa are quite promising. The vaccine IC43, a recombinant outer membrane protein (Opr) targeting the Oprs of P. aeruginosa, completed a phase II trial, in which no significant difference was found in P. aeruginosa infection rates, although it was associated with a lower mortality rate [14]. Despite evident immunogenicity between days 7 and 14, P. aeruginosa infection occurred prior to the development of IgG immune response. ExoU is the most important virulence mechanism with impact on outcomes, although research efforts have been focused in blocking PcrV [14]. KB001, a pegylated anti-PcrV MA fragment to the type III secretion system (TTSS) of P. aeruginosa involved with the release of exotoxins, failed to show improvement in lung inflammation and reduction in colonization in patients with cystic fibrosis [14]. Other MAs include IgY avian polyclonal antibody (phase III clinical trial—NCT01455675 completed—results pending) and MEDI3902 binding to PcrV and Psl-mediating cytotoxicity (in phase II trial NCT02696902 in mechanically ventilated patients as of writing of this review) [14]. Modulators of bacterial cell wall, transport, signaling, or virulence have also been used against Pseudomonas spp. infections. Inhibitors of quorum sensing have demonstrated activity against biofilm formation and secretion of virulence factors (elastase—Las, rhamnolipids—Rhl, and Pseudomonas quinolone signal systems—PQS) [14]. However, until now, none of them has been evaluated in clinical practice. In the ICU, only macrolides were associated with a trend to prevent VAP and reduction of quorum sensing-regulated virulence factors activation [14]. Neutralization of virulence effectors inhibit P. aeruginosa LasB elastase targeting the ability of bacteria to evade the immune system, while Gallium, an iron mimetic, inhibits in vitro P. aeruginosa growth and biofilm formation [14]. Bacteriophages prevent damage to normal flora, do not infect the eukaryotic cells, and are not associated with rapid proliferation inside the host bacteria. The use of monophage vs cocktail treatment, the genomic identification (to minimize the risk of horizontal gene transfer to bacteria), and stability to reach the site of infection remain important challenges for the future [14].

An antagonistic interaction to the yeast between Candida spp. and Pseudomonas aeruginosa and the role of cell wall components, quorum sensing molecules, phenazines, fatty acid metabolites, and competition for iron are well described [15]. The role of newly identified elements of P. aeruginosa QS network, oxylipin production by both species, as well as the genetic and phenotypic plasticity of those pathogens reflect suggested future perspectives. The prevention of P. aeruginosa resistance deals with microbiological monitoring, antimicrobial stewardship, and infection control programs (environmental cleaning/disinfection, hand hygiene, and education of personnel), while the discrimination between colonization and infection is crucial (supplementary text).

In-depth understanding of the pathogenicity and resistance mechanisms of P. aeruginosa and its interactions with the host led to the development of several non-antibiotic approaches. Future treatments of P. aeruginosa infections, particularly by XDR strains, will probably adopt the aforementioned advancements with or without the addition of antibiotics.

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Conflicts of interest

The authors declare that they have no conflict of interest.