Carbapenem-resistant Pseudomonas aeruginosa in intensive care units increase mortality as an emerging global threat

Dear Editor,

Pseudomonas aeruginosa is an opportunistic Gram-negative bacteria known to rapidly colonize both living and nonliving surfaces, causing a wide range of diseases, including healthcare-associated infections in ICUs. Mainly due to its versatile and ubiquitous features, as well as its ability to invade all types of body parts and survive in harsh environments, P. aeruginosa is extremely difficult to control in hospital settings1. Furthermore, it is evident that P. aeruginosa is known to infect immunocompromised individuals such as cancer patients and those hospitalized for critical illnesses obtaining interventions in ICUs. For instance, according to a recent European Centre for Disease Prevention and Control report on infections acquired in the ICU in 18 European countries, P. aeruginosa was the most common cause of ventilator-associated pneumonia and the fifth most prevalent in ICU-acquired bloodstream infections with 20–50% mortality2. In particular, it should be noted that ICU admission, intubation, or the use of invasive devices are frequently linked to the risk of acquiring multidrug-resistant P. aeruginosa (MDRPA) (Fig. 1)3.

Figure 1.

Virtuous prevention and control strategies for carbapenem-resistant Pseudomonas aeruginosa in ICU.

Ever since the first discovery of penicillin by Alexander Fleming in 1928, numerous broad-spectrum antibacterial drugs, including beta-lactams such as carbapenems, have been in use throughout the world. Carbapenems are the most effective antimicrobial agents for the treatment of severe infections, and are typically reserved to treat multidrug-resistant bacterial infections as last resort treatment options4. However, the prevalence of carbapenem-resistant P. aeruginosa (CRPA) has been increasing rapidly in recent years, ranging from 10 to 50% globally5, posing a significant antibacterial resistance threat, which is mainly attributed to its intrinsic resistance against a wide variety of antimicrobials and its ability to easily acquire antibiotic resistance6,7. It is also evident that CRPA infections significantly increase mortality in those critically ill patients.

MDRPA and CRPA initially emerged right after imipenem and meropenem were introduced as treatment options for P. aeruginosa infections. The emerging imipenem resistance has been attributed to the outer membrane protein (Opr) inactivation, whereas meropenem resistance mainly results from efflux overexpression systems5. Moreover, CRPA also stems from combined effects of porin mutations, overexpression of the MexA-MexB-OprM efflux pump, overproduction of beta-lactamases (particularly AmpC), inactivation of the outer membrane protein D (OprD) and/or changes to the penicillin-binding proteins8.

The predominant carbapenem resistance determinants carried by P. aeruginosa are often encoded on incompatibility (IncP) type plasmids, bla _VIM gene containing class I integrons, and other mobile genetics elements, which enhance the organism’s capability to spread resistance among multiple species. Such resistance determinants further diminish the therapeutic efficacy of aminoglycosides and fluoroquinolones in addition to altering the efficacy of commonly used antipseudomonal agents, including cefepime, ceftazidime, piperacillin–tazobactam, along with the recently introduced beta-lactam/beta-lactamase inhibitor (BL–BLI) combinations such as imipenem–relebactam, ceftolozane–tazobactam, and ceftazidime–avibactam9. Hence, all these therapeutic ineffectiveness and their association with nosocomial spread demand the implementation of prompt infection prevention interventions.

The WHO has designated CRPA as a ‘priority pathogen,’ which is a serious health concern; consequently, it is urgent and vital to look for novel treatment options10. The emergence and rise of CRPA have been mostly attributed to metallo-beta-lactamases (MBLs), primarily Verona integron-mediated (VIM) MBLs. Commonly isolated VIM-2 and VIM-4-producing CRPA often belong to clonal complexes 111 and 235, respectively. The commonest forms, bla _VIM-2 and bla _VIM-4, are typically associated with class 1 integron5. There is also an increase in carbapenemase production among isolates of CRPA due to the increased use of carbapenems to treat MDRPA infections. These carbapenemases include Ambler class A KPC-type and GES-type beta-lactamases, as well as Ambler class B or metallo-beta-lactamases (MBLs), mainly VIM (Verona integrin-encoded MβL), IMP (imipenemase), and NDM (New Delhi MβL) types, which are important because of their efficacy in hydrolyzing carbapenems11,12.

Recently, outbreaks were caused by the spread of high-risk CRPA clones such as ST175 and ST244 that produce class B carbapenemases (VIM and IMP), which have been linked with high rates of mortality and morbidity, particularly in healthcare settings, necessitating a collaborative effort on infection prevention and management through the development of new therapeutic strategies13.

The approved BL–BLI combinations, ceftazidime–avibactam (CZA), ceftolozane–tazobactam (C/T), meropenem–vaborbactam (M/V), and imipenem–cilastatin–relebactam (I/R) have demonstrated in-vitro effectiveness in treating CRPA in the clinical setting; however, emerging resistance and cross-resistance to all agents has been reported. On the other hand, cefiderocol, a siderophore cephalosporin, was recently developed as a single antibiotic without a beta-lactamase inhibitor to overcome all mechanisms of carbapenem resistance in CRPA, mainly due to its potent activity and proven efficacy in clinical studies, particularly among patients with critical infections in the hospital setting such as ICU14. Furthermore, with its unique mechanism of cell entry through iron transport channels, cefiderocol exhibits bypassing most common beta-lactam resistance mechanisms and displayed better in-vitro activity against isolates resistant to BL–BLI combinations15. To sum up, more clinical data from large-scale surveillance are needed to ensure the efficacy and safety profile of novel CRPA treatment options, such as cefiderocol. Furthermore, delicate infection prevention and control strategies should be implemented in the healthcare setting to reduce emerging mortality due to CRPA, particularly among patients undergoing invasive clinical procedures and critical illnesses in ICU. Continued monitoring of evolving carbapenem resistance mechanisms and research focused on novel approaches, including phage therapy and nanoparticulate treatment options, are vital to lessening the impact CRPA infections have on critical patients and the general healthcare system

Ethical approval

Not applicable.

Sources of funding

No source of funding.

Author contribution

M.S.: investigation, and writing – original draft preparation; M.B.: conceptualization, data collection, visualization, and original draft preparation; J.A.: conceptualization, writing – reviewing and editing, and supervision.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest.

Research registration unique identifying number (UIN)

None

Guarantor

Melaku Belete.

Data availability statement

All data are available in the manuscript.