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BACTERIOLOGY

Pseudomonas aeruginosa in the healthcare facility setting

Spagnolo, Anna Maria; Sartini, Marina; Cristina, Maria Luisa

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Reviews in Medical Microbiology: July 2021 - Volume 32 - Issue 3 - p 169-175
doi: 10.1097/MRM.0000000000000271
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Abstract

Introduction

Pseudomonas aeruginosa is a Gram-negative pathogen that has become an important cause of infection in humans and can be associated with significant morbidity and mortality.

This microorganism is one of the most frequent and severe causes of hospital-acquired infections, particularly affecting immunocompromised (especially neutropenic) and intensive care unit (ICU) patients. The majority of P. aeruginosa strains are resistant to most antibiotics currently in use.

Due to a range of mechanisms for adaptation, survival and resistance to multiple classes of antibiotics, infections by P. aeruginosa strains can be life-threatening and are emerging as a global public health threat [1].

The aim of the present narrative review is to describe P. aeruginosa in the healthcare facility settings, and the related infectious risk. Searches were carried out in PubMed.gov and Scopus for published papers on P. aeruginosa bacteriology, ecology, healthcare reservoir, healthcare infection, prevention and control measures.

Bacteriology and ecology

Microorganisms belonging to the species P. aeruginosa are straight or slightly curved, rod-shaped bacteria, 1.5 ± 3 μm long and between 0.5 and 0.7 μm wide; they are Gram-negative aerobes motile via one or more polar flagella.

P. aeruginosa is characterised by the production of pigments: pyocyanin, which is water-soluble and green–blue in colour, pyorubin, which is water-insoluble and reddish-brown in colour, and fluorescein or pyoverdin, which is water-soluble, ranging from yellow–green to yellow–brown in colour and fluorescent in the ultraviolet. More than 90% of the strains produce pyocyanin and there seems to be an inverse relationship between growth rates and production of pyocyanin, with increases in the production of this pigment corresponding to decreases in the growth rate [2].

The pathogenic profile of P. aeruginosa is related to its complex genome and a large and variable arsenal of virulence factors [3]. A mucoid layer of exopolysaccharide (d-mannuronic and l-guluronic acetylated acids polymer) is particularly evident in recent isolates of P. aeruginosa obtained from the sputum of cystic fibrosis (CF) patients; the weight of this layer in these patients can quantitatively exceed that of the whole bacterial cell; subsequent subculture yields the more typical, nonmucoid forms. The exopolysaccharide allows bacteria to adhere to one another, forming microcolonies in the lungs of patients with P. aeruginosa pneumonia; the surrounding anionic matrix also protects the large bacterial mass from phagocytes and the action of antibodies and complement. The fimbriae present in the majority of P. aeruginosa strains are adhesion and colonisation factors. An extracellular toxic protein, called exotoxin A, is, moreover, produced by more than 90% of P. aeruginosa isolates [4]. These are just a few examples of the virulence factors produced by this microbial species.

P. aeruginosa is a microorganism characterised by a high capacity for adaptation. It is found in surface, waste and marine water, soil, vegetation and all humid environments in general [2]. In nature, free-living amoebae of the genus Acanthamoeba feed on Pseudomonas spp. [5], which are widely distributed in the environment. However, some Pseudomonas spp. have evolved to become resistant to predation by amoebae, as demonstrated by the isolation of Acanthamoebae naturally infected with P. aeruginosa[6]. Free-living amoebae might therefore also act as a reservoir for some amoeba-resistant strains of Pseudomonas spp., as has been shown for Legionella spp. [7,8].

P. aeruginosa can sometimes be found in the normal gut and skin microflora, as well as in the environment. The ability to use simple organic molecules as a carbon and energy source also encourages these microorganisms to multiply in solutions, which would otherwise be incapable of sustaining high bacterial growth, such as mild antiseptics, saline solutions and soaps [4].

P. aeruginosa has several survival mechanisms, such as biofilm formation, quorum sensing (QS), viable but not culturable (VBNC) state and antibiotic resistance mechanisms [9,10].

P. aeruginosa is one of the typical microorganisms of biofilms; it can readily adhere to surfaces that are wet or in contact with liquids [2]. Biofilm development can be affected by the genetic makeup of both P. aeruginosa isolates and environmental conditions, as well as the interaction between the two [3].

The shift of bacteria from the planktonic mode of growth to the biofilm state is dependent on the production of adhesins and extracellular matrix components that serve as a scaffold and encase the bacteria in the biofilms. The matrix in P. aeruginosa biofilms consists mainly of polysaccharides, proteins, extracellular DNA and lipids, and its composition is strain-dependent, and also depends on the growth conditions and the age of the biofilm [11].

Quantitatively, in the biofilm matrix of P. aeruginosa, extracellular DNA (essential for the adhesion of microorganisms and their intercellular cohesion) is six times more abundant than proteins and eighteen times more abundant than carbohydrates. Its origin was confirmed as being genomic. Nucleic acids can arise either from the lysis of a part of sessile cells or from an active secretion by living bacteria through merging membrane vesicles [12].

The biofilm is rich in nutrients and can protect microorganisms against disinfectants used; it is also a potential site for the transfer of virulence factors and resistance to antibiotics [13], thereby promoting the persistence of bacteria, including multidrug resistant organisms, in the environment [14].

QS, a cell density-based intercellular communication system, plays a key role in regulating bacterial virulence and biofilm formation. The QS network of P. aeruginosa is organised in a multilayered hierarchy consisting of at least four interconnected signalling mechanisms [15].

A further survival mechanism of P. aeruginosa is a VBNC state. In times of stress or as part of its natural life cycle, P. aeruginosa can adopt a VBNC state, which renders it undetectable by current conventional culturing methods and makes it highly resistant to antibiotic treatment. Specific conditions can resuscitate these coccoid VBNC P. aeruginosa cells, which returns them to their active, virulent rod-shaped form [10].

The ubiquitous presence of P. aeruginosa, as well as its prevalence and persistence in clinical settings including intrinsic resistance to therapeutics, is attributed to its extraordinary survival capability by recruiting an arsenal of responsive mechanisms [1].

Antibiotic resistance in Pseudomonas aeruginosa

According to the WHO, P. aeruginosa is one of the antimicrobial-resistant bacteria that poses the greatest threat to human health [10].

P. aeruginosa can have multiple intrinsic or acquired mechanisms of resistance, frequently with high resistance rates to various antimicrobial classes [16].

P. aeruginosa is intrinsically resistant to the majority of antimicrobial agents due to its selective ability to prevent various antibiotic molecules from penetrating its outer membrane or to extrude them if they enter the cell. The antimicrobial groups that remain active include some fluoroquinolones (e.g. ciprofloxacin and levofloxacin), aminoglycosides (e.g. gentamicin, tobramycin and amikacin), some β-lactams (e.g. piperacillin-tazobactam, ceftazidime, cefepime, ceftolozane-tazobactam, ceftazidime-avibactam, imipenem, meropenem, doripenem) and polymyxins. The resistance of P. aeruginosa to these agents can be acquired through one or more of several mechanisms, including modified antimicrobial targets, active efflux, reduced permeability and degrading enzymes [17].

The European Antimicrobial Resistance Surveillance Network of the European Centre for Disease Prevention and Control (ECDC) (EARS-Net) 2018 has reported that 32.1% of P. aeruginosa isolates in the European Union/European Economic Area were resistant to at least one of the antimicrobial groups under regular surveillance (piperacillin-tazobactam, fluoroquinolones, ceftazidime, aminoglycosides and carbapenems). Resistance to two or more antimicrobial groups was common and seen in 19.2% of all tested isolates. Large inter-country variations were seen for all antimicrobial groups, with generally higher resistance percentages reported from southern and eastern Europe than northern Europe [17].

In recent years, the worldwide spread of the so-called ‘high-risk clones’ of multidrug-resistant or extensively drug-resistant (MDR/XDR) P. aeruginosa has become a public health threat that needs to be studied and managed with urgency and determination [18,19]. The lack of therapeutic alternatives means that infections caused by these antibiotic-resistant bacteria pose a considerable threat regarding morbidity and mortality worldwide [18].

A recent (2017) large-scale multicentre study (51 hospitals) of P. aeruginosa infections performed in Spain showed that up to 26.2% of the isolates were classified as MDR, 17.3% as XDR and 0.1% as pandrug resistant. Carbapenemases/extended-spectrum beta-lactamases were detected in 3.1% of the isolates, including VIM, IMP, GES, PER and OXA enzymes. The most frequent clone among the XDR isolates was ST175 (40.9%), followed by CC235 (10.7%), ST308 (5.2%) and CC111 (4.0%) [20].

The spread of Verona integron-encoded metallo-β-lactamase-producing carbapenem-resistant Pseudomonas aeruginosa (VIM-CRPA) is particularly worrying.

CRPA infections are difficult to cure, both because well tolerated and effective therapeutic options are often unavailable, and because the associated mortality is higher than in infections by carbapenem-susceptible P. aeruginosa[16,21].

Several foci of VIM-CRPA have been reported associated with healthcare in European countries (Belgium, France, Germany, Greece, Hungary, Italy, Netherlands and Spain), some of which could be related to invasive medical procedures. High-risk clones have, moreover, been described for P. aeruginosa, characterised by hospital spread all over the world and the ability to rapidly acquire other antibiotic resistance genes [16].

According to the ECDC's ‘Surveillance of antimicrobial resistance in Europe 2018’ [17], carbapenem resistance in invasive isolates of P. aeruginosa in the EU/EEA averaged 17.2% in 2018, with wide variations between countries, from 0% in Iceland to 55.1% in Romania. In Italy, 15.8% of 3014 invasive isolates of P. aeruginosa were resistant to carbapenems.

Pseudomonas aeruginosa reservoirs in healthcare setting

Confirmed environmental reservoirs of P. aeruginosa in a healthcare setting are numerous and include aerosols, potable water, faucets/taps, sink and shower drains, respiratory equipment, humidifiers, endoscopes and endoscope washers, water baths and hydrotherapy pools, and bathing basins [22–27].

In a previous study [28], we carried out postreprocessing microbiological surveillance of duodenoscopes in a digestive endoscopy unit over a 3-year period. One hundred and twenty-four microbiological samples were taken from the duodenoscopes (62 from the distal end and 62 from the instrument channel), following postreprocessing.

P. aeruginosa was found in high concentrations (10–2500 CFU/duodenoscope); also with regard to the distal end, the antibiogram revealed that 60% of the samples positive for P. aeruginosa contained strains resistant to multiple antibiotics (including carbapenems).

P. aeruginosa can be transmitted by a number of routes, including patient-to-patient and environmental contamination [22,29,30]. Due to its adaptable nature and high surviving ability, it can survive on dry inanimate surfaces in a hospital environment from 6 h to 6 months [31].

A further means of spreading infections that cannot be ignored is the hands of operators which can be contaminated following contact with a colonised/infected patient, or after using contaminated soap, cream or water.

Although several possible reservoirs of P. aeruginosa have been described in a healthcare setting, hospital water has been shown to be a significant source of healthcare-associated infections caused by P. aeruginosa, through direct contact (bathing, contact with mucous membranes or surgical sites, or through splashing from water), medical devices/equipment rinsed with contaminated water and indirect contact via healthcare workers’ hands after washing in contaminated water, from surfaces contaminated with water or from contaminated equipment [14]. P. aeruginosa can persist in hospital water for long periods [32].

Hota et al.[33] reported contamination of an ICU sink with a multidrug-resistant Pseudomonas strain; fluorescein injection into sink drains demonstrated splash-back up to 1 m from the sink when the water was running.

It is estimated that most Pseudomonas water system contamination is confined to the distal 2 m of the water system [34].

P. aeruginosa is among the species frequently found in dental unit waterlines [5,35–37], where it is capable of forming biofilms on the inner surface of narrow-bore plastic tubing that carries water to the high-speed handpiece, air/water syringe and ultrasonic scaler. A very small lumen size (0.5–2 mm), high surface to volume ratio (6:1), low throughput, the materials of which the tubing is made and water stagnation in DUWL, when units are not in use, further encourages biofilm growth [36].

In our previous study [35], we evaluated the level of bacterial contamination in 30 dental units, including P. aeruginosa. The mean concentration of P. aeruginosa in water from handpieces was 25.13 ± CFU/100 ml.

A study conducted by Jensen et al.[38] evaluated the presence of P. aeruginosa in water from dental sessions attended by CF patients. Water samples were obtained from triple function syringes, turbines, handpiece contra-angles and ultrasonic scalers. Sputum samples from each CF patient were also examined for P. aeruginosa each month, before and after the dental appointment. At least in one case, genotypically identical (RFLP, pulsed-field gel electrophoresis) P. aeruginosa strains were found both in water from the dental equipment and in the CF patients’ sputum.

Pseudomonas aeruginosa infections

P. aeruginosa infections are rare in healthy individuals and are generally mild. Skin infections contracted in swimming pools, for example, are short-lived and self-limiting.

Severe infections usually affect immunocompromised patients or those with chronic debilitating diseases; it is the patient's general condition, and therefore the state of health, that generally determines the outcome of P. aeruginosa infection [4].

Its significance as a pathogen is exacerbated by its resistance to antibiotics, virulence factors and its ability to adapt to a wide range of environments [27].

Patients with carbapenem-resistant and extensive β-lactam resistant P. aeruginosa infections are at increased risk of a delay in receiving appropriate antimicrobial therapy, resulting in prolonged hospitalisation, increased risk of subsequent antibiotic-resistant infections, morbidity and mortality [39].

The capacity to form biofilms provides the bacteria with an enormous advantage when establishing infections within susceptible hosts [3]. One biofilm-related infection of particular medical concern is P. aeruginosa biofilms in the lungs of CF patients [9]. Once established, P. aeruginosa in CF patients’ airways develops into chronic infections and generally persists indefinitely. Ultimately, 60–80% of adults will become chronically infected with P. aeruginosa[40]. Acquisition of P. aeruginosa is associated with increased morbidity and mortality in patients with CF, and is an important factor in the development and progression of CF respiratory disease [3].

Patients with malignant blood cancers (such as leukaemias), neutropenia following immunosuppressive therapy or bacteraemic pneumonia are also considered at risk. In the same way, prolonged venous or urinary catheterisation, invasive surgical procedures, severe burns and wounds allow the microorganism to pass through the protective layers of the skin and colonise the various tissues; this can lead to septicaemia [4].

P. aeruginosa can cause infections of the urinary tract, burns and wounds, corneal ulcers and keratitis, septicaemias, gastroenteritis in neonates, abscesses, bronchopneumonia and meningitis. Its pathogenic activity is due to its invasive capacity and the production of extracellular substances, such as exotoxin A [2].

P. aeruginosa can also be responsible for highly destructive infections of the eyes, following the use of contaminated ophthalmological solutions or as a result of severe facial burns [4].

Among Gram-negative infections, P. aeruginosa is one of the most common Gram-negative bacteria causing nosocomial and healthcare-associated infections in hospitalised patients. MDR P. aeruginosa infections in the hospital setting are associated with poor outcomes including increased resource utilisation and costs, morbidity, and mortality. The increasing level of resistance in MDR P. aeruginosa is often attributed to patient-to-patient transmission of resistant strains as well as newly acquired resistance owing to previous antibiotic exposure. [41].

Kanayama et al.[42] described a multidrug-resistant Pseudomonas aeruginosa (MDRP) outbreak in a long-term care facility. A total of 23 MDRP cases were identified; environmental samples were obtained from affected wards. The screening for carbapenemases by a multiplex PCR revealed that all isolates harboured the GES-type β-lactamase gene. Pulsed-field gel electrophoresis results indicated that all of the analysed isolates from cases and environmental samples were either indistinguishable or closely related with high similarity (≥95%).

Bajolet et al.[43] reported an outbreak at a hospital in Reims, France, in 2011, which was traced to a single endoscope contaminated with extended-spectrum beta-lactamase-producing P. aeruginosa.

P. aeruginosa is a microorganism frequently involved in infections occurring in patients admitted to ICU. This microorganism has been shown to be among the five most frequently involved in nosocomial infections in ICU, such as pneumonia, urinary tract infections, and surgical site/soft tissue and blood infections [25].

A study by Kikuchi et al. described an outbreak of clonally related strains of CRPA in 20 ICU patients. Patients with positive respiratory specimens were mechanically ventilated, which included re-used disinfected bite blocks during intubation. Swabs from patient beds, tracheal endoscopes, oxygen masks, body fluid aspiration tubes, humidified air inhalation tubes and bite block apparatus were cultured.

P. aeruginosa was detected on the bite block apparatus, even though this had been disinfected after each use. It was therefore hypothesised that cracks in the rubber portion of bite blocks, or crevices between the rubber and metallic components of bite blocks, cannot be completely disinfected [44].

An observational prospective multicentre study, entitled DYNAPYO, was performed, involving 10 French ICUs for a 5-month study period [45]. The overall prevalence of P. aeruginosa carriage was 15.3%. Risk factors associated with patient colonisation were: use of inactive antibiotics against P. aeruginosa (HR = 1.60 [1.15–2.21], P < 0.01), and mechanical invasive ventilation (HR = 4.70 [2.66–8.31], P < 0.0001). Tap water contamination at the entry point in the patient room enhanced the risk of colonisation by +66% (HR = 1.66; 95% CI = [1.01 ± 2.75]).

Water sources and water-related devices are often contaminated with pathogens responsible for healthcare-associated infections, including P. aeruginosa[46–48]. This may occur when microorganisms survive treatment protocols or via endpoint contamination [49].

Salm et al.[50] reported an outbreak of clonal multidrug-resistant P. aeruginosa in a surgical, interdisciplinary ICU in a tertiary care hospital. The authors found evidence of a transmission route associated with working procedures at sinks, in particular the use of the sinks for grooming patients.

A recent study [51] described an outbreak of infection by extensively drug-resistant P. aeruginosa in the burns unit of a university hospital in Barcelona (Spain). The outbreak was caused by a strain of P. aeruginosa susceptible only to colistin. Ten patients were infected or colonised and two of them died. The same strain was detected on several taps and drains in different rooms in the unit.

Prevention and control measures of nosocomial infections by P. aeruginosa

According to WHO guidelines, measures to prevent the transmission of multiresistant P. aeruginosa in healthcare facilities should include at least the following: hand hygiene (with the appropriate use of alcohol-based solutions), contact precautions, patient isolation (single room or cohort), environmental cleanliness and surveillance.

The ECDC recommends improving and increasing surveillance, screening and preventive isolation in healthcare facilities of patients who have been transferred from, or been in recent contact with, hospitals or other healthcare facilities in countries with a high prevalence of multiresistant bacteria such as P. aeruginosa, in order to limit their spread. The availability of documentation relating to infection by multiresistant P. aeruginosa or to carrier status, at the time patients are transferred, would help implement rapidly and effectively measures to prevent the spread of the microorganism [16,52,53].

ICUs require particular infection prevention measures (different from standard care wards) in order to take into account the increased risk of infection and transmission associated with ICU-specific working procedures (e.g. ventilator support and central-line catheters).

Furthermore, to mitigate risks associated with the bacterial contamination of water supply and distribution systems and associated equipment, WHO guidelines for the prevention of nosocomial infections by water-borne microorganisms state the need for the adoption, in order to manage water-related risk in healthcare facilities, of a water safety plan (WSP), the essential components of which are active monitoring of infections, adopting sanitisation procedures, maintenance and testing of the water supply and scheduled testing of water taken from the most significant points in the hospital water system. Validation procedures should be established to ensure that the WSP is working effectively and meets health-based targets [54,55].

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

Source of funding: None declared.

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Keywords:

multidrug resistance; nosocomial infection risk; Pseudomonas aeruginosa

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.