**8. Conclusions**

*Pseudomonas aeruginosa* - Biofilm Formation, Infections and Treatments

not yet been identified [137].

**7.5 Ceftolozane-tazobactam**

tions showed promising results.

**7.6 Ceftazidime-avibactam**

**7.4 Arikayce ™**

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

Arikayce™ has been approved by the FDA for the treatment of *Mycobacterium avium* complex (MAC) lung disease, and is a liposomal amikacin treatment. Clinical trials for this drug and its efficacy in the treatment of *P. aeruginosa* in patients with cystic fibrosis have been performed. While these are early phases and some experiments would have to resolve the drawbacks of this compound in order to improve

To resolve *P. aeruginosa* antimicrobial resistance mechanisms, such as changes in porine permeability and upregulation of efflux pumps, ceftolozane-tazobactam is being created. Due to a higher affinity for all essential PBPs, including PBP1b, PBP1c and PBP3, this drug has an intrinsically potent anti-pseudomonal effect [139]. Ceftolozane/ Tazobactam has been shown to have a strong in vitro activity against most strains of MDR *P. aeruginosa* [including strains developing extendedspectrum β-lactamase (ESBL) but not carbapenemase]. The therapeutic use of ceftolozane-tazobactam in complicated intra-abdominal and urinary tract infections has been suggested by the FDA [140]. In addition, a study is currently underway for the treatment of HAP, including ventilator-associated pneumonia (VAP). In 71 percent of patients with MDR *P. aeruginosa* infections, evidence from real-world trials using ceftolozane-tazobactam for the treatment of MDR *P. aeruginosa* infec-

Ceftazidime-avibactam is a novel combination of β-lactam / BLI approved for the treatment of complicated urinary tract infections (UTIs) and complicated intra-abdominal infections by the Food and Drug Administration (FDA) and *European Medicines Agency* (EMA). In vitro studies have shown that the combination of ceftazidime-avibactam is highly effective against KPC- producing *Klebsiella pneumoniae* carbapenemase (KPCs), oxacillinase (OXA), extended- spectrum β-lactamases (ESBLs) and AmpC enzymes producing Enterobacteriaceae. The drug does not, however, have any action against metallo-beta β- lactamases (MBL, VIM and NDM) and avibactam does not have any improved activity against *P. aeruginosa* [141]. In phase III research compared ceftazidime-avibactam to meropenem (NTC01808092), the efficacy of ceftazidime-avibactam against VAP was analyzed [142]. The predominant isolated baseline gram-negative pathogens were *K. pneumoniae* and *P. aeruginosa*, with 28% of patients possessing a non-susceptible isolate of 1% ceftazidime. 356 patients in the clinically evaluable population were treated with ceftazidime-avibactam and 370 with meropenem. The research met the non-inferiority criterion for ceftazidime-avibactam as there was no disparity in the outcome between the groups. In addition, the efficacy of ceftazidime-avibactam

safety, some experimental clinical trials have been performed [138].

**90**

Treatment of infections with *P. aeruginosa* continues to be significant challenging. Improving the early diagnosis and empirical treatment of serious *P. aeruginosa* infections is an urgent need. First, to quickly announce the detection and susceptibility results for *Pseudomonas* in blood cultures and other clinically important cultures, matrix-assisted-laser-desorption-ionization time-of-flight mass spectrometry (MALDI-TOF) and modern molecular techniques should be routinely introduced. However, in order to decide if such diagnostic methods have a real effect on hospitalization time and patient mortality, controlled trials would be required. Secondly, more studies are urgently required to classify patients at risk of infection with MDR *P. aeruginosa* (bloodstream infections, urinary tract infections) based on clinical risk factors. Ultimately, clinical response depends on factors such as underlying diseases, seriousness of infection, form of infection, adequate control of the source, and response to prior antibiotics. There is an immediate need to determine the true impact of the latest anti-Pseudomonas drugs recently approved for the treatment of these infections on patient outcomes. To date, however, due to high cost, side effects and safety issues, few of these newer methods have continued to clinical practice.
