Pseudomonas aeruginosa: Infection Risks, Challenges, and Breakthroughs for Health Care Professionals

Pseudomonas aeruginosa

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Pseudomonas aeruginosa (P aeruginosa) was first described by Charles-Emmanuel Sédillot, who noted that patients' surgical dressings turned blue-green and had a sweet grape-like odor.¹ It is a rod-shaped, gram-negative bacteria from the family Pseudomonadaceae. Although it is a facultative aerobe that uses oxygen, it is capable of anaerobic respiration. P aeruginosa can catabolize a wide range of organic molecules for nutrition, allowing it to thrive in various environments such as soil, water, and human skin and mucosa.

P aeruginosa has been described as one of the most virulent opportunistic gram-negative bacteria.² The ability of P aeruginosa to cause a wide variety of infections is due to its large number of virulence factors. Some of them include the following:

• Apoptosis-inducing cytokines such as ToxA, Azurin, and Pyocyanin
• Membrane-associated cytokines, such as lipopolysaccharide
• Type III secretion system exotoxins

Infections Caused By Pseudomonas aeruginosa

P aeruginosa can thrive in diverse environments such as hot tubs, respirators, and even mops in the hospital, increasing the possibility of exposure and infection.¹ As an opportunistic pathogen, it is known to cause mortality in immunocompromised individuals and is the cause of most cases of hospital-acquired pneumonia and respiratory failure.

Certain immunocompromised patients, such as those with drug-induced neutropenia, those undergoing chemotherapy, and solid organ transplant recipients, are more vulnerable to P aeruginosa infections. The main reason for this increased risk in solid organ transplant recipients is the use of immunosuppressants. These patients also receive prophylactic antibiotics, which increases the risk of infection with antibiotic-resistant strains.

Acute infections Caused By P aeruginosa

P aeruginosa can cause serious acute infections such as pneumonia, urinary tract infection, corneal ulcers and keratitis in individuals wearing contact lenses, and bloodstream infections.

Pneumonia has been a major burden on health care, with antibiotic-resistant strains further complicating treatment. P aeruginosa has been one of the leading causes of different types of pneumonia. A multinational study of 1173 patients from 54 countries found that P aeruginosa was responsible for 11.3% of community-acquired pneumonia, with 2% of patients suffering from antibiotic-resistant P aeruginosa.³ It was the leading cause of hospital-acquired pneumonia from 1997 to 2008. A recent meta-analysis in Japan showed that P aeruginosa was responsible for 29.2% of ventilator-acquired pneumonia cases, making it responsible for most cases.⁴

Urinary tract infections caused by P aeruginosa are associated with high morbidity and mortality among elderly patients in the hospital.⁵ Isolates of P aeruginosa from patients showed higher antibiotic resistance than Escherichia coli, which is the most common cause of urinary tract infections (UTIs). Elderly patients were also seen to have recurrent urinary tract infections UTIs, possibly due to P aeruginosa invading the urinary epithelial cells. It is also a cause of complicated UTIs, especially in patients with catheters, and can lead to life-threatening pyelonephritis.¹

Infectious keratitis is a sight-threatening condition common in individuals wearing contact lenses. A multicenter study in Iran found that P aeruginosa was responsible for 71.9% of the cases that tested positive for gram-negative bacteria.⁶ It has also been associated with severe keratitis.¹

Chronic infections caused by P aeruginosa

Cystic fibrosis patients are commonly affected by P aeruginosa infections.⁷ The lungs of patients with cystic fibrosis are a favorable environment for bacterial growth and colonization due to a thick mucus layer, which reduces bacterial internalization, hinders pathogen clearance, and inhibits antimicrobial peptides. A chronic infection with P aeruginosa is generally not responsive to antibiotic therapy, resulting in reduced pulmonary functions and death.

P aeruginosa prefers wounds to grow and colonize, and chronic wounds are no exception.¹ Chronic wounds such as diabetic foot ulcers, pressure ulcers, and venous leg ulcers are commonly infected by P aeruginosa. Evidence suggests that P aeruginosa may slow wound healing and tissue repair and exacerbate tissue damage. Wounds infected with P aeruginosa were also found to be larger than those infected with other organisms, such as Staphylococcus aureus.

Challenges in treating these infections

Antibiotic resistance is a significant challenge in all bacterial infections, but more so in infections caused by P aeruginosa. It is resistant to beta-lactamase, quinolones, and aminoglycosides.⁷ Due to this challenge and the severity of infections caused by this organism, it was placed among other priority pathogens for whom new antibiotics are urgently needed, according to the World Health Organization and the CDC.¹ These priority pathogens are also known as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).

P aeruginosa has 3 types of mechanisms to counter an antibiotic attack—intrinsic resistance, acquired resistance, and adaptive resistance. P aeruginosa possesses a high level of intrinsic resistance to multiple antibiotics.⁷ Intrinsic resistance refers to a bacteria’s innate ability to reduce the efficacy of an antibiotic due to its structural or functional characteristics. The intrinsic resistance of P aeruginosa includes the expression of effluent pumps that remove antibiotics from the cell, the production of antibiotic-inactivating enzymes, and low other membrane permeability.

Acquired resistance of P aeruginosa consists of mutations and horizontal transfer of resistance genes. The formation of biofilm in the lungs of infected patients is used as adaptive resistance. The biofilm works as a diffusion barrier and limits antibiotic access to bacterial cells. Multidrug-resistant persistent cells can form in these biofilms and are responsible for recurrent infections.

Latest breakthroughs and strategies

Rising rates of antibiotic resistance are a significant burden on health care facilities and the economy. While the development of new therapies has been slow, there is a push to develop new antibiotics and other antibacterial therapies.

In recent years, new novel antibiotics with in vitro activity against gram-negative bacteria, including P aeruginosa, have been approved.⁸ Ceftobiprole, a fifth-generation cephalosporin, has been approved for use in patients with community—and hospital-acquired pneumonia and has shown potent activity against several gram-negative bacteria, such as P aeruginosa and Haemophilus influenza. Ceftolozane-tazobactam, a combination of modified cephalosporin with a beta-lactamase inhibitor, has also shown superiority against other drugs in various trials.

A study found that the stimulator of the interferon gene (STING), a pattern recognition receptor, suppressed inflammatory cytokine expression and promoted bacterial killing, reducing the severity of keratitis caused by P aeruginosa.⁹

Phage therapies against pseudomonas aeruginosa have shown promising results. An advantage of phage therapy over antibiotics is that phage therapy can be used against the biofilm produced by the bacteria.¹⁰ A previous study used a cocktail of 4 bacteriophages (Pa193, Pa204, Pa222, and Pa223) against P aeruginosa isolated from patients with chronic rhinosinusitis. All 4 phases alone and in combination were able to significantly decrease the rate of biofilm production after 24 and 48 hours of treatment. It also suggested that using a cocktail increased activity due to a range of hosts and prevented the formation of phage-resistant bacteria. Another study studied the effects of PB1-like, phiKZ-like, and LUZ24-like phages against multidrug-resistance P aeruginosa. LUZ24-like phage was the most effective in destroying the biofilm, which the researchers say is due to its small size. The larger phiKZ-like had the least effect on the biofilm. They also noted that phases may not significantly impact high-density biofilms, but they prevent further accumulation and diffusion of biofilms.

P aeruginosa is a highly virulent pathogen that frequently infects immunocompromised individuals. It is also inherently resistant to many antibiotics, making it challenging to treat. While research for novel antibiotics and antibacterial therapies is underway, we urgently need new therapies to be approved for use in patients with multidrug-resistant P aeruginosa.

References

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2. Wood SJ, Goldufsky JW, Seu MY, Dorafshar AH, Shafikhani SH. Pseudomonas aeruginosa cytotoxins: Mechanisms of cytotoxicity and impact on inflammatory responses. Cells. 2023;12(1):195-195. doi:10.3390/cells12010195
3. Restrepo MI, Babu BL, Reyes LF, et al. Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia: A multinational point prevalence study of hospitalised patients. Eur Respir J. 2018;52(2):1701190. doi:10.1183/13993003.01190-2017
4. Moro H, Aoki N, Matsumoto H, et al. Bacterial profiles detected in ventilator-associated pneumonia in Japan: A systematic review. Respir Investig. 2024;62(3):365-368. doi:10.1016/j.resinv.2024.01.012
5. Newman J, Floyd R, Fothergill J. Invasion and diversity in Pseudomonas aeruginosa urinary tract infections. J Med Microbiol. 2022;71(3). doi:10.1099/jmm.0.001458
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8. Bassetti M, Magnè F, Giacobbe DR, Bini L, Vena A. New antibiotics for Gram-negative pneumonia. Eur Respir Rev. 2022;31(166). doi:10.1183/16000617.0119-2022
9. Chen K, Fu Q, Liang S, et al. Stimulator of interferon genes promotes host resistance against Pseudomonas aeruginosa keratitis. Front Immunol. 2018;9. doi:10.3389/fimmu.2018.01225
10. Chegini Z, Khoshbayan A, Taati Moghadam M, Farahani I, Jazireian P, Shariati A. Bacteriophage therapy against Pseudomonas aeruginosa biofilms: A review. Ann Clin Microbiol Antimicrob. 2020;19(1). doi:10.1186/s12941-020-00389-5