The goal of our study was to compare the antibiotic resistance profiles of P. aeruginosa isolates from ICU and non-ICU patients in a tertiary care university hospital, and to evaluate potential empirical treatment options. Our findings indicate that resistance to ciprofloxacin was higher in non-ICU patients compared to those in the ICU, while resistance to piperacillin-tazobactam, MDR P. aeruginosa, and carbapenemase-producing P. aeruginosa strains, were higher in ICU patients. Based on the resistance profiles of P. aeruginosa in our study, the recommended first-line treatments would be effective empirically against the wild-type strains, only 40% of strains in ICU and 65% of strains in non-ICU. However, DTR P. aeruginosa strains, which represent 21% in ICU and 19% in non-ICU, would remain inadequately treated. Our study shows that using the novel beta-lactam-beta-lactamase inhibitor combinations of ceftolozane-tazobactam and ceftazidime-avibactam, whose effectiveness against DTR P. aeruginosa remains preserved, as empirical treatment, would improve the adequacy by 21% in ICU patients and 19% in non-ICU, compared to recommended first-line treatments.
P. aeruginosa displays resistance to a variety of antibiotics, including β-lactams, quinolones and aminoglycosides. Various mechanisms can contribute to resistance to beta-lactams. For example, a chromosomal AmpC, which, when exposed to certain beta-lactams such as imipenem, clavulanic acid and cephamycine, confers resistance to beta-lactams, cephalosporins and aztreonam, though sparing carbapenems11. Some P. aeruginosa isolates produce extended-spectrum-β-lactamases (ESBLs) which confer a high degree of resistance to the majority of β-lactam antibiotics, including penicillins, cephalosporins and aztreonam12. Meanwhile, carbapenem resistance is mostly caused by mutations inactivating OprD, a gene coding for D2 protein, conferring high level of resistance especially to imipenem, though not affecting other beta-lactams13. Another mechanism of resistance to beta-lactams is overexpression of MexAB-OprM, an active efflux mechanism consequent of gene mutations of transcriptional regulators, and conferring reduced susceptibility to ticarcillin, aztreonam and meropenem14. Resistance to fluoroquinolones results mainly from mutations in the target enzymes DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) and in overexpression of MexAB-OprM active efflux15. Aminoglycosides resistance occurs through various mechanisms such as reduced permeability, efflux (MexXY-OprM), ribosomal mutations and enzyme modifications. However, the latter is the most predominant, mainly through plasmid-mediated acquisition of inactivating enzymes aminoglycoside acetyltransferase (AAC) and aminoglycoside nucleotidyltransferase (ANT)16. Meanwhile, resistance to polymyxin B and gentamicin is a result of overexpression of OprH consequent of Mg2+ starvation17.
For DTR P. aeruginosa, the novel beta-lactam-beta-lactamase inhibitor combination ceftolozane/tazobactam represents an effective option as assessed by ESCMID guidelines. However, at the time of publication, the ESCMID guidelines indicated that there is insufficient evidence supporting the use of ceftazidime-avibactam for treating infections caused by DTR P. aeruginosa18. Moreover, in a multicenter retrospective cohort of ICU patients with infections to P. aeruginosa (XDR 48.4% and MDR 36.8%), 71.6% of patients exhibited a favorable clinical response, and no outcome differences in the case of ceftolozane/tazobactam therapy19. Therefore, according to our study, using ceftolozane/tazobactam as empiric therapy may be considered advantageous, especially in ICU settings where DTR P. aeruginosa represents 21% of strains.
Nevertheless, the efficacy of ceftolozane/tazobactam in MDR strains may be compromised through a number of mechanisms including production of Pseudomonas-derived cehalosporinase (PDC), acquisition of transferable ESBLs or carbapenemases. The GERPA multicenter study which collected 420 strains nonsusceptible to ceftazidime and/or imipenem from 36 French hospital laboratories, indicated that some strains were resistant to ceftolozane/tazobactam before the introduction of ceftolozane/tazobactam and ceftazidime/avibactam in France. This implies that older antipseudomonal beta-lactams select for ceftolozane/tazobactam resistance through cross resistance20.
In our study, the distribution of strains was 30% in ICU and 70% in non-ICU patients, consistent with the ERACE-PA Global Surveillance program’s findings from 12 different countries, suggesting that P. aeruginosa is not an ICU-confined pathogen21. Similarly, a study comprising 13 hospitals in the United States found that P. aeruginosa has a high prevalence (65%) outside of the ICU22. However, our study showed that MDR P. aeruginosa was more frequently isolated in the ICU. In fact, P. aeruginosa with limited treatment options are often reported in ICUs and in long-term acute care hospitals, likely due to the use of broad-spectrum antimicrobials and mechanical ventilation23,24. Risk factors for acquiring MDR/XDR-P. aeruginosa infections include chronic pulmonary diseases (e.g., cystic fibrosis) which increase colonization risk, and previous exposition to antipseudomonal carbapenems and fluoroquinolones within the past three months25,26. Interestingly, high-level resistance to ciprofloxacin is frequently associated with high-level resistance to antipseudomonal agents such as piperacillin-tazobactam (90%) and carbapenems (88 to 90%), suggesting shared resistance mechanisms like overproduction of efflux pumps27,28. Moreover, P. aeruginosa can form biofilms on medical devices, resist disinfection methods, transiently colonize the intestinal tract, and spread among immunocompromised patients29. Additionally, P. aeruginosa with resistance to multiple antibiotics has been a common cause of severe superinfections in critically ill patients with COVID-1930. In fact, the CDC reported a 35% increase in hospital-onset MDR P. aeruginosa infections between the years 2019–202031, potentially due to antibiotic, to treat secondary bacterial infections, and mechanical ventilation, a known source of nosocomial infections particularly ventilator-associated pneumoniae (VAP)32. According to the ECDC, P. aeruginosa accounts for 16.1% of VAP in ICUs33.
Our study’s main strength is its detailed exploration of P. aeruginosa resistance profiles within a low-to-middle income country, where research on antimicrobial resistance epidemiology remains sparse. This investigation is particularly relevant given the region’s high travel volume, diverse expatriate and refugee populations, and liberal antibiotic prescribing practices, all of which can contribute to the dissemination of resistant strains. However, our findings from Hôtel-Dieu de France, a major hospital in Beirut, may not be representative of other healthcare settings within the country. This limitation highlights the need for a multi-center surveillance network across Lebanon. Given the pathogen’s role as a significant cause of healthcare-associated infections, especially strains with limited treatment options, such surveillance is essential for guiding effective antimicrobial stewardship and infection control strategies.
In conclusion, antibiotic-resistant P. aeruginosa is emerging as a significant threat with severe healthcare implications. Infection prevention becomes critically important, as this pathogen can quickly develop resistance to even the newest antibiotics. Treatment decisions should be made with caution, conserving newer antibiotics for cases of DTR P. aeruginosa and selecting appropriate therapies based on the specific resistance mechanisms involved. New antibiotics should be used judiciously, empirically in cases where local resistance patterns suggest a high risk of DTR infections, or as definitive treatments when susceptibility testing confirms resistance to other antibiotics and sensitivity to the new agent. The limited treatment options for antibiotic-resistant P. aeruginosa heighten the risk of treatment failures and increase the burden on healthcare systems, emphasizing the need for implementing effective antimicrobial strategies and prudent antibiotic stewardship.
