**7.1 Doripenem**

*Pseudomonas aeruginosa* - Biofilm Formation, Infections and Treatments

recombinant vaccine IC43, containing OprF and OprI.

patients has become a great challenge for effective vaccination [128].

**6. Role of combination therapy** *versus* **monotherapy**

was suggested.

**5.7 Vaccine strategy**

Recent studies by Xu et al. [124], have indicated that probiotics can be used by patients infected by COVID 19 to prevent secondary infections. There was intestinal microbial dysbiosis in some patients with COVID-19. In all patients, nutritional and gastrointestinal functions must be measured. To control the composition of the intestinal microbiota and reduce the risk of secondary infection due to bacterial translocation, nutritional support and application of probiotics

The concept of a vaccine strategy is to avoid infection until it can be produced. The production of vaccines aims to prevent and decrease infections of *P. aeruginosa* [125]. However, no approved vaccine against this pathogen is yet available. *P. aeruginosa* antigens, which are responsible for pathogenesis, induce potent immune responses. LPS O-antigen, polysaccharide protein conjugates, outer membrane proteins OprF and OprI, type III secretion system portion PcrV, flagella, pili, DNA, live-attenuated *P. aeruginosa* and whole killed cells are possible candidates for *P. aeruginosa* vaccines [126]. Among the potential *P. aeruginosa* vaccines, phase III clinical trials in CF patients were performed only with the flagella vaccine and the

Related to the ability of this pathogen to undergo phenotypic changes in variable environmental conditions, the existing vaccines for *P. aeruginosa* demonstrate poor efficacy in clinical trials. For example, *P. aeruginosa* strains downregulate the expression of highly immunogenic virulence factors in CF patients' lungs, such as LPS O-antigen, type III secretion systems, flagella and pili [127]. In addition, impaired mechanisms of host protection often reduce vaccination effectiveness. Due to the CF lungs having an altered mucus layer, impaired phagocytosis, and dysregulated inflammatory responses, including aberrant cytokine and chemokine production, and reduced phagocyte recruitment, the lung microenvironment in CF

Early administration of adequate antibiotic therapy was associated with a favorable clinical outcome, especially among critically ill patients with serious *P. aeruginosa* infections [129]; on the other hand, delays in administering adequate antibiotic therapy were associated with a substantial increase in mortality. The progressive rise in antibiotic resistance in *P. aeruginosa* has been established in recent years as the key explanation for the inadequacy of antibiotics, with a negative effect on

The evidence available indicates that the greatest advantage of combination therapy derives from an increased probability of selecting an appropriate agent during empirical therapy, rather than avoiding resistance during definitive therapy or benefiting from synergistic action in vitro. Therefore, researchers recommend early administration of a combination regimen when *P. aeruginosa* is suspected, followed by a prompt de-escalation when the antimicrobial susceptibility test becomes available, to balance between early antibiotic administration and the risk of resistance selection. An approach consisting of the prescription of an anti-pseudomonal beta-lactam (piperacillin / tazobactam, ceftolozane / tazobactam, ceftazidime, cefepime, or carbapenem) plus a second (aminoglycoside or fluoroquinolone)

**88**

patient survival [130].

anti-pseudomonal agent is encouraged.

Doripenem is a new carbapenem antibiotic with wide spectrum activity against gram-negative and gram-positive bacteria by binding to penicillin-binding proteins by inhibiting bacterial cell wall synthesis; it has been approved for the treatment of complicated intra-abdominal infection and urinary tract infection by the US Food and Drug Administration (FDA) [131]. Except for the metallo-β-lactamases of class B, doripenem is resistant to hydrolysis by several β-lactamases. Importantly, compared to other carbapenem antibiotics such as meropenem and imipenem, the in vitro antibacterial activity of doripenem against the *P. aeruginosa* isolates from CF patients was found to be more active [132]. In addition, the effectiveness of doripenem was tested in patients with *P. aeruginosa* ventilator-associated pneumonia, a phase III clinical trial of patients with *P. aeruginosa* ventilator-associated pneumonia found that patients treated with doripenem had higher rates of cure compared to patients treated with imipenem. Of note, headache, nausea, diarrhea, rash, and phlebitis are among the side effects of doripenem [133].

### **7.2 Plazomicin**

Plazomicin is a semisynthetic aminoglycoside antibiotic of the next generation that is synthetically derived from the natural product sisomicin. A wide range of aminoglycoside modifying enzymes, but not 16S rRNA ribosomal methyltransferases, are able to resist plazomicin [134]. Plazomicin exhibits potent in vitro activity against both gram-negative and gram-positive bacterial pathogens and has an activity close to that of amikacin against strains of multidrug-resistant *P. aeruginosa*. In addition, Pankuch et al., reported in vitro synergistic activity of plazomicin against clinical isolates of *P. aeruginosa* in combination with cefepime, doripenem, imipenem or piperacillin-tazobactam and no antagonism was observed in this study, indicating that plazonmicin is a possible candidate for combination therapy in the treatment of infections with multidrug-resistant *P. aeruginosa*. Plazomicin can cause nephrotoxic and ototoxic effects that are mild to moderate [135].

## **7.3 POL7001**

As a novel class of antibiotics against *P. aeruginosa*, protein epitope mimetic (PEM) molecules have emerged; some PEM molecules inhibit the transfer of LPS to the outer bacterial membrane [136]. A macrocycle molecule belonging to the PEM antibiotic family is POL7001. The efficacy of POL7001 was tested by Cigana et al.,

both in vitro and in murine *P. aeruginosa* acute and chronic pneumonia models. They observed that *P. aeruginosa* multidrug-resistant isolates were susceptible to POL7001 in CF patients, and that POL7001-treated mice had substantially decreased bacterial burden and decreased levels of lung inflammation during acute and chronic *P. aeruginosa* infection. POL7001 as a novel therapeutic agent for potential clinical trials is indicated by the new mode of action, effective pulmonary delivery and potent in vitro and in vivo activity. The side effects of POL7001 have not yet been identified [137].
