Pseudomonas aeruginosa

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Pseudomonas aeruginosa
Pseudomonas aeruginosa and Staphylococcus aureus colonies.jpg
P. aeruginosa colony (right) and S. aureus colony (left) on trypticase soy agar
Scientific classification Red Pencil Icon.png
Domain: Bacteria
Phylum: Proteobacteria
Class: Gammaproteobacteria
Order: Pseudomonadales
Family: Pseudomonadaceae
Genus: Pseudomonas
Species:
P. aeruginosa
Binomial name
Pseudomonas aeruginosa
(Schröter 1872)
Migula 1900
Synonyms
  • Bacterium aeruginosumSchroeter 1872
  • Bacterium aeruginosumCohn 1872
  • Micrococcus pyocyaneusZopf 1884
  • Bacillus aeruginosus(Schroeter 1872) Trevisan 1885
  • Bacillus pyocyaneus(Zopf 1884) Flügge 1886
  • Pseudomonas pyocyanea(Zopf 1884) Migula 1895
  • Bacterium pyocyaneum(Zopf 1884) Lehmann and Neumann 1896
  • Pseudomonas polycolorClara 1930
  • Pseudomonas vendrelli nomen nudum 1938

Pseudomonas aeruginosa is a common encapsulated, Gram-negative, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes.

Bacterial capsule

The bacterial capsule is a very large structure of many bacteria. It is a polysaccharide layer that lies outside the cell envelope, and is thus deemed part of the outer envelope of a bacterial cell. It is a well-organized layer, not easily washed off, and it can be the cause of various diseases.

Gram-negative bacteria group of bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation

Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the gram-staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall sandwiched between an inner cytoplasmic cell membrane and a bacterial outer membrane.

Bacillus (shape) rod-shaped bacterium (not to be confused with the taxon Bacilli)

A bacillus or bacilliform bacterium is a rod-shaped bacterium or archaeon. Bacilli are found in many different taxonomic groups of bacteria. However, the name Bacillus, capitalized and italicized, refers to a specific genus of bacteria. The name Bacilli, capitalized but not italicized, can also refer to a less specific taxonomic group of bacteria that includes two orders, one of which contains the genus Bacillus. When the word is formatted with lowercase and not italicized, 'bacillus', it will most likely be referring to shape and not to the genus at all. Bacilliform bacteria are also often simply called rods when the bacteriologic context is clear. Sea Bacilli usually divide in the same plane and are solitary, but can combine to form diplobacilli, streptobacilli, and palisades.

Contents

The organism is considered opportunistic insofar as serious infection often occurs during existing diseases or conditions – most notably cystic fibrosis and traumatic burns. It generally affects the immunocompromised but can also infect the immunocompetent as in hot tub folliculitis. Treatment of P. aeruginosa infections can be difficult due to its natural resistance to antibiotics. When more advanced antibiotic drug regimens are needed adverse effects may result.

Opportunistic infection

An opportunistic infection is an infection caused by pathogens that take advantage of an opportunity not normally available, such as a host with a weakened immune system, an altered microbiota, or breached integumentary barriers. Many of these pathogens do not cause disease in a healthy host that has a normal immune system. However, a compromised immune system, which is seriously debilitated and has lowered resistance to infection, a penetrating injury, or a lack of competition from normal commensals presents an opportunity for the pathogen to infect.

Disease abnormal condition negatively affecting organisms

A disease is a particular abnormal condition that negatively affects the structure or function of part or all of an organism, and that is not due to any external injury. Diseases are often construed as medical conditions that are associated with specific symptoms and signs. A disease may be caused by external factors such as pathogens or by internal dysfunctions. For example, internal dysfunctions of the immune system can produce a variety of different diseases, including various forms of immunodeficiency, hypersensitivity, allergies and autoimmune disorders.

Cystic fibrosis Autosomal recessive disease

Cystic fibrosis (CF) is a genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Different people may have different degrees of symptoms.

It is citrate, catalase, and oxidase positive. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in low-oxygen atmospheres, thus has colonized many natural and artificial environments. It uses a wide range of organic material for food; in animals, its versatility enables the organism to infect damaged tissues or those with reduced immunity. The symptoms of such infections are generalized inflammation and sepsis. If such colonizations occur in critical body organs, such as the lungs, the urinary tract, and kidneys, the results can be fatal. [1] Because it thrives on moist surfaces, this bacterium is also found on and in medical equipment, including catheters, causing cross-infections in hospitals and clinics. It is also able to decompose hydrocarbons and has been used to break down tarballs and oil from oil spills. [2] P. aeruginosa is not extremely virulent in comparison with other major pathogenic bacterial species – for example Staphylococcus aureus and Streptococcus pyogenes – though P. aeruginosa is capable of extensive colonization, and can aggregate into enduring biofilms. [3]

Catalase protein-coding gene in the species Homo sapiens

Catalase is a common enzyme found in nearly all living organisms exposed to oxygen. It catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting the cell from oxidative damage by reactive oxygen species (ROS). Likewise, catalase has one of the highest turnover numbers of all enzymes; one catalase molecule can convert millions of hydrogen peroxide molecules to water and oxygen each second.

Skin flora community of microorganisms of the skin

The term skin flora refers to the microorganisms which reside on the skin, typically human skin.

Hypoxia refers to low oxygen conditions. Normally, 20.9% of the gas in the atmosphere is oxygen. The partial pressure of oxygen in the atmosphere is 20.9% of the total barometric pressure. In water however, oxygen levels are much lower, approximately 1%, and fluctuate locally depending on the presence of photosynthetic organisms and relative distance to the surface.

Nomenclature

A culture dish with Pseudomonas Pseudomonas aeruginosa culture.JPG
A culture dish with Pseudomonas

The word Pseudomonas means "false unit", from the Greek pseudēs (Greek: ψευδής, false) and (Latin : monas, from Greek: μονάς, a single unit). The stem word mon was used early in the history of microbiology to refer to germs, e.g., kingdom Monera.

Ancient Greek Version of the Greek language used from roughly the 9th century BCE to the 6th century CE

The Ancient Greek language includes the forms of Greek used in Ancient Greece and the ancient world from around the 9th century BCE to the 6th century CE. It is often roughly divided into the Archaic period, Classical period, and Hellenistic period. It is antedated in the second millennium BCE by Mycenaean Greek and succeeded by medieval Greek.

Microbiology study of microscopic organisms

Microbiology is the study of microorganisms, those being unicellular, multicellular, or acellular. Microbiology encompasses numerous sub-disciplines including virology, parasitology, mycology and bacteriology.

Germ theory of disease

The germ theory of disease is the currently accepted scientific theory for many diseases. It states that microorganisms known as pathogens or "germs" can lead to disease. These small organisms, too small to see without magnification, invade humans, other animals, and other living hosts. Their growth and reproduction within their hosts can cause disease. "Germ" may refer to not just a bacterium but to any type of microorganism or even non-living pathogen that can cause disease, such as protists, fungi, viruses, prions, or viroids. Diseases caused by pathogens are called infectious diseases. Even when a pathogen is the principal cause of a disease, environmental and hereditary factors often influence the severity of the disease, and whether a potential host individual becomes infected when exposed to the pathogen.

The species name aeruginosa is a Latin word meaning verdigris ("copper rust"), referring to the blue-green color of laboratory cultures of the species. This blue-green pigment is a combination of two metabolites of P. aeruginosa, pyocyanin (blue) and pyoverdine (green), which impart the blue-green characteristic color of cultures. Another assertion is that the word may be derived from the Greek prefix ae- meaning "old or aged", and the suffix ruginosa means wrinkled or bumpy. [4]

Verdigris green copper-based pigment

Verdigris is the common name for a green pigment obtained through the application of acetic acid to copper plates or the natural patina formed when copper, brass or bronze is weathered and exposed to air or seawater over time. It is usually a basic copper carbonate, but near the sea will be a basic copper chloride. If acetic acid is present at the time of weathering, it may consist of copper(II) acetate.

Pyocyanin chemical compound

Pyocyanin (PCN) is one of the many toxins produced and secreted by the Gram negative bacterium Pseudomonas aeruginosa. Pyocyanin is a blue, secondary metabolite with the ability to oxidise and reduce other molecules and therefore can kill microbes competing against P. aeruginosa as well as mammalian cells of the lungs which P. aeruginosa has infected during cystic fibrosis. Since pyocyanin is a zwitterion at blood pH, it is easily able to cross the cell membrane. There are three different states in which pyocyanin can exist; oxidized, monovalently reduced or divalently reduced. Mitochondria play an important role in the cycling of pyocyanin between its redox states. Due to its redox-active properties, pyocyanin generates reactive oxygen species.

Pyoverdine chemical compound

Pyoverdines are fluorescent siderophores produced by certain pseudomonads. Pyoverdines are important virulence factors, and are required for pathogenesis in many biological models of infection. Their contributions to bacterial pathogenesis include providing a crucial nutrient, regulation of other virulence factors, supporting the formation of biofilms, and are increasingly recognized for having toxicity themselves.

The names pyocyanin and pyoverdine are from the Greek, with pyo-, meaning "pus", [5] cyanin, meaning "blue", and verdine, meaning "green".[ citation needed ] Pyoverdine in the absence of pyocyanin is a fluorescent-yellow color.

Gram-stained P. aeruginosa bacteria (pink-red rods) Pseudomonas aeruginosa Gram.jpg
Gram-stained P. aeruginosa bacteria (pink-red rods)

Biology

Genome

The genome of P. aeruginosa consists of a relatively large circular chromosome (5.5–6.8 Mb) that carries between 5,500 and 6,000 open reading frames, and sometimes plasmids of various sizes depending on the strain; [6] Comparison of 389 genomes from different P. aeruginosa strains showed that just 17.5% is shared. This part of the genome is the P. aeruginosa core genome. [7]

strain:VRFPA04C3719PAO1PA14PACS2
Chromosome size (bp)6,818,0306,222,0976,264,4046,537,6486,492,423
ORFs5,9395,5785,5715,9055,676

Metabolism

P. aeruginosa is a facultative anaerobe, as it is well adapted to proliferate in conditions of partial or total oxygen depletion. This organism can achieve anaerobic growth with nitrate or nitrite as a terminal electron acceptor. When oxygen, nitrate, and nitrite are absent, it is able to ferment arginine and pyruvate by substrate-level phosphorylation. [8] Adaptation to microaerobic or anaerobic environments is essential for certain lifestyles of P. aeruginosa, for example, during lung infection in cystic fibrosis and primary ciliary dyskinesia, where thick layers of lung mucus and bacterially-produced alginate surrounding mucoid bacterial cells can limit the diffusion of oxygen. P. aeruginosa growth within the human body can be asymptomatic until the bacteria form a biofilm, which overwhelms the immune system. These biofilms are found in the lungs of people with cystic fibrosis and primary ciliary dyskinesia, and can prove fatal. [9] [10] [11] [12] [13] [14]

Cellular cooperation

P. aeruginosa relies on iron as a nutrient source to grow. However, iron is not easily accessible because it is not commonly found in the environment. Iron is usually found in a largely insoluble ferric form. [15] Furthermore, excessively high levels of iron can be toxic to P. aeruginosa. To overcome this and regulate proper intake of iron, P. aeruginosa uses siderophores, which are secreted molecules that bind and transport iron. [16] These iron-siderophore complexes, however, are not specific. The bacterium that produced the siderophores does not necessarily receive the direct benefit of iron intake. Rather, all members of the cellular population are equally likely to access the iron-siderophore complexes. Members of the cellular population that can efficiently produce these siderophores are commonly referred to as cooperators; members that produce little to no siderophores are often referred to as cheaters. Research has shown when cooperators and cheaters are grown together, cooperators have a decrease in fitness, while cheaters have an increase in fitness. [17] The magnitude of change in fitness increases with increasing iron limitation. [18] With an increase in fitness, the cheaters can outcompete the cooperators; this leads to an overall decrease in fitness of the group, due to lack of sufficient siderophore production. These observations suggest that having a mix of cooperators and cheaters can reduce the virulent nature of P. aeruginosa. [17]

Pathogenesis

Phagocytosis of P. aeruginosa by neutrophil in patient with bloodstream infection (Gram stain) Pseudomonas aeruginosa smear Gram 2010-02-10.JPG
Phagocytosis of P. aeruginosa by neutrophil in patient with bloodstream infection (Gram stain)

An opportunistic, nosocomial pathogen of immunocompromised individuals, P. aeruginosa typically infects the airway, urinary tract, burns, and wounds, and also causes other blood infections. [19]

InfectionsDetails and common associationsHigh-risk groups
Pneumonia Diffuse bronchopneumonia Cystic fibrosis patients
Septic shock Associated with a purple-black skin lesion ecthyma gangrenosum Neutropenic patients
Urinary tract infectionUrinary tract catheterization
Gastrointestinal infection Necrotising enterocolitis Premature infants and neutropenic cancer patients
Skin and soft tissue infectionsHemorrhage and necrosisPeople with burns or wound infections

It is the most common cause of infections of burn injuries and of the outer ear (otitis externa), and is the most frequent colonizer of medical devices (e.g., catheters). Pseudomonas can be spread by equipment that gets contaminated and is not properly cleaned or on the hands of healthcare workers. [20] Pseudomonas can, in rare circumstances, cause community-acquired pneumonias, [21] as well as ventilator-associated pneumonias, being one of the most common agents isolated in several studies. [22] Pyocyanin is a virulence factor of the bacteria and has been known to cause death in C. elegans by oxidative stress. However, salicylic acid can inhibit pyocyanin production. [23] One in ten hospital-acquired infections is from Pseudomonas. Cystic fibrosis patients are also predisposed to P. aeruginosa infection of the lungs. P. aeruginosa may also be a common cause of "hot-tub rash" (dermatitis), caused by lack of proper, periodic attention to water quality. Since these bacteria like moist environments, such as hot tubs and swimming pools, they can cause skin rash or swimmer's ear. [20] Pseudomonas is also a common cause of postoperative infection in radial keratotomy surgery patients. The organism is also associated with the skin lesion ecthyma gangrenosum. P. aeruginosa is frequently associated with osteomyelitis involving puncture wounds of the foot, believed to result from direct inoculation with P. aeruginosa via the foam padding found in tennis shoes, with diabetic patients at a higher risk.

Toxins

P. aeruginosa uses the virulence factor exotoxin A to inactivate eukaryotic elongation factor 2 via ADP-ribosylation in the host cell, much as the diphtheria toxin does. Without elongation factor 2, eukaryotic cells cannot synthesize proteins and necrotise. The release of intracellular contents induces an immunologic response in immunocompetent patients. In addition P. aeruginosa uses an exoenzyme, ExoU, which degrades the plasma membrane of eukaryotic cells, leading to lysis. Increasingly, it is becoming recognized that the iron-acquiring siderophore, pyoverdine, also functions as a toxin by removing iron from mitochondria, inflicting damage on this organelle. [24] [25]

Phenazines

Phenazines are redox-active pigments produced by P. aeruginosa. These pigments are involved in quorum sensing, virulence, and iron acquisition. [26] P. aeruginosa produces several pigments all produced by a biosynthetic pathway: pyocyanin, 1-hydroxyphenazine, phenazine-1-carboxamide, 5-methylphenazine-1-carboxylic acid betaine, and aeruginosin A. Two operons are involved in phenazine biosynthesis: phzA1B1C1D1E1F1G1 and phzA2B2C2D2E2F2G2. [27] [28] These operons convert a chorismic acid to the phenazines mentioned above. Three key genes, phzH, phzM, and phzS convert phenazine-1-carboxylic acid to the phenazines mentioned above. Though phenazine biosynthesis is well studied, questions remain as to the final structure of the brown phenazine pyomelanin.

When pyocyanin biosynthesis is inhibited, a decrease in P. aeruginosa pathogenicity is observed in vitro . [28] This suggests that pyocyanin is most responsible for the initial colonization of P. aeruginosain vivo.

Triggers

With low phosphate levels, P. aeruginosa has been found to activate from benign symbiont to express lethal toxins inside the intestinal tract and severely damage or kill the host, which can be mitigated by providing excess phosphate instead of antibiotics. [29]

Plants and invertebrates

In higher plants, P. aeruginosa induces soft rot, for example in Arabidopsis thaliana (Thale cress) [30] and Lactuca sativa (lettuce). [31] [32] It is also pathogenic to invertebrate animals, including the nematode Caenorhabditis elegans , [33] [34] the fruit fly Drosophila [35] and the moth Galleria mellonella. [36] The associations of virulence factors are the same for plant and animal infections. [31] [37]

Quorum sensing

Regulation of gene expression can occur through cell-cell communication or quorum sensing (QS) via the production of small molecules called autoinducers. The extracellular accumulation of these molecules signals to bacteria to alter gene expression and coordinate behavior. P. aeruginosa employs five interconnected QS systems – lasRl, rhlRl, PQS, iqs and pch – that each produce unique signaling molecules. [38] Detection of these molecules indicates P. aeruginosa is growing as biofilm within the lungs of cystic fibrosis patients. [39] QS is known to control expression of a number of virulence factors, including the pigment pyocyanin. Another form of gene regulation that allows the bacteria to rapidly adapt to surrounding changes is through environmental signaling. Recent studies have discovered anaerobiosis can significantly impact the major regulatory circuit of QS. This important link between QS and anaerobiosis has a significant impact on production of virulence factors of this organism. [40] Garlic experimentally blocks quorum sensing in P. aeruginosa. [41]

Biofilms formation and cyclic-di-GMP

As in most Gram negative bacteria, P. aeruginosa biofilm formation is regulated by one single molecule: cyclic-di-GMP. At low c-di-GMP concentration, P. aeruginosa has a free-swimming mode of life. But when c-di-GMP level increases, P. aeruginosa start to establish sessile communities on surfaces. The intracellular concentration of c-di-GMP increases within seconds when P. aeruginosa touches a surface (e.g.: a rock, plastic, host tissues...). [42] This activates the production of adhesives pili, that serve as "anchors" to stabilize the attachment of P. aeruginosa on the surface. At later stages, bacteria will start attaching irreversibly by producing a strongly adhesive matrix. At the same time, c-di-GMP represses the synthesis of the flagellar machinery, preventing P. aeruginosa to swim. When suppressed, the biofilms are less adherent and easier to treat. The biofilm matrix of P. aeruginosa is composed of nucleic acids, amino acids, carbohydrates, and various ions. It mechanically and chemically protects P. aeruginosa from aggression by the immune system and some toxic compounds. P. aeruginosa biofilm's matrix is composed of 2 types of sugars (or "exopolysacharides") named PSL and PEL:

Upon certain cues or stresses, P. aeruginosa revert the biofilm program and detach. Recent studies have shown that the dispersed cells from P. aeruginosa biofilms have lower c-di-GMP levels and different physiologies from those of planktonic and biofilm cells. [45] [46] Such dispersed cells are found to be highly virulent against macrophages and C. elegans, but highly sensitive towards iron stress, as compared with planktonic cells. [45]

Biofilms and treatment resistance

Biofilms of P. aeruginosa can cause chronic opportunistic infections, which are a serious problem for medical care in industrialized societies, especially for immunocompromised patients and the elderly. They often cannot be treated effectively with traditional antibiotic therapy. Biofilms seem to protect these bacteria from adverse environmental factors. P. aeruginosa can cause nosocomial infections and is considered a model organism for the study of antibiotic-resistant bacteria. Researchers consider it important to learn more about the molecular mechanisms that cause the switch from planktonic growth to a biofilm phenotype and about the role of QS in treatment-resistant bacteria such as P. aeruginosa. This should contribute to better clinical management of chronically infected patients, and should lead to the development of new drugs. [40]

Recently, scientists have been examining the possible genetic basis for P. aeruginosa resistance to antibiotics such as tobramycin. One locus identified as being an important genetic determinant of the resistance in this species is ndvB, which encodes periplasmic glucans that may interact with antibiotics and cause them to become sequestered into the periplasm. These results suggest a genetic basis exists behind bacterial antibiotic resistance, rather than the biofilm simply acting as a diffusion barrier to the antibiotic. [47]

Diagnosis

Production of pyocyanin, water-soluble green pigment of P. aeruginosa (left tube) Pseudomonas aeruginosa pyocyanin.jpg
Production of pyocyanin, water-soluble green pigment of P. aeruginosa (left tube)

Depending on the nature of infection, an appropriate specimen is collected and sent to a bacteriology laboratory for identification. As with most bacteriological specimens, a Gram stain is performed, which may show Gram-negative rods and/or white blood cells. P. aeruginosa produces colonies with a characteristic "grape-like" or "fresh-tortilla" odor on bacteriological media. In mixed cultures, it can be isolated as clear colonies on MacConkey agar (as it does not ferment lactose) which will test positive for oxidase. Confirmatory tests include production of the blue-green pigment pyocyanin on cetrimide agar and growth at 42 °C. A TSI slant is often used to distinguish nonfermenting Pseudomonas species from enteric pathogens in faecal specimens.

When P. aeruginosa is isolated from a normally sterile site (blood, bone, deep collections), it is generally considered dangerous, and almost always requires treatment.[ citation needed ] However, P. aeruginosa is frequently isolated from nonsterile sites (mouth swabs, sputum, etc.), and, under these circumstances, it may represent colonization and not infection. The isolation of P. aeruginosa from nonsterile specimens should, therefore, be interpreted cautiously, and the advice of a microbiologist or infectious diseases physician/pharmacist should be sought prior to starting treatment. Often, no treatment is needed.

Identification

TestResults
Gram Stain-
Oxidase+
Indole Production-
Methyl Red-
Voges-Proskaeur-
Citrate+
Hydrogen Sulfide Production-
Urea Hydrolysis-
Phenylalanine Deaminase-
Lysine Decarboxylase-
Motility+
Gelatin Hydrolysis+
Acid from lactose-
acid from glucose+
acid from maltose-
acid from mannitol+
acid from sucrose-
nitrate reduction+
DNAse-
Lipase+
Pigment+ (bluish green pigmentation)
Catalase+
HemolysisBeta/variable

[48] P. aeruginosa is a Gram-negative, aerobic (and at times facultatively anaerobic), rod-shaped bacterium with unipolar motility. [49] It has been identified as an opportunistic pathogen of both humans and plants. [50] P. aeruginosa is the type species of the genus Pseudomonas . [51]

Identification of P. aeruginosa can be complicated by the fact individual isolates often lack motility. Furthermore, mutations in the gene lasR drastically alter colony morphology and typically lead to failure to hydrolyze gelatin or hemolyze.[ citation needed ]

In certain conditions, P. aeruginosa can secrete a variety of pigments, including pyocyanin (blue), pyoverdine (yellow and fluorescent), pyorubin (red), and pyomelanin (brown). These can be used to identify the organism. [52]

Pseudomonas aeruginosa fluorescence under UV illumination Pseudomonas aeruginosa.JPG
Pseudomonas aeruginosa fluorescence under UV illumination

Clinical identification of P. aeruginosa may include identifying the production of both pyocyanin and fluorescein, as well as its ability to grow at 42 °C. P. aeruginosa is capable of growth in diesel and jet fuels, where it is known as a hydrocarbon-using microorganism, causing microbial corrosion. [53] It creates dark, gellish mats sometimes improperly called "algae" because of their appearance. [ citation needed ]

Treatment

Many P. aeruginosa isolates are resistant to a large range of antibiotics and may demonstrate additional resistance after unsuccessful treatment. It should usually be possible to guide treatment according to laboratory sensitivities, rather than choosing an antibiotic empirically. If antibiotics are started empirically, then every effort should be made to obtain cultures (before administering first dose of antibiotic), and the choice of antibiotic used should be reviewed when the culture results are available.

The antibiogram of P. aeruginosa on Mueller-Hinton agar Pseudomonas aeruginosa antibiogram.jpg
The antibiogram of P. aeruginosa on Mueller-Hinton agar

Due to widespread resistance to many common first-line antibiotics, carbapenems, polymyxins, and more recently tigecycline were considered to be the drugs of choice; however, resistance to these drugs has also been reported. Despite this, they are still being used in areas where resistance has not yet been reported. Use of β-lactamase inhibitors such as sulbactam has been advised in combination with antibiotics to enhance antimicrobial action even in the presence of a certain level of resistance. Combination therapy after rigorous antimicrobial susceptibility testing has been found to be the best course of action in the treatment of multidrug-resistant P. aeruginosa. Some next-generation antibiotics that are reported as being active against P. aeruginosa include doripenem, ceftobiprole, and ceftaroline. However, these require more clinical trials for standardization. Therefore, research for the discovery of new antibiotics and drugs against P. aeruginosa is very much needed. Antibiotics that may have activity against P. aeruginosa include:

As fluoroquinolones are one of the few antibiotic classes widely effective against P. aeruginosa, in some hospitals, their use is severely restricted to avoid the development of resistant strains. On the rare occasions where infection is superficial and limited (for example, ear infections or nail infections), topical gentamicin or colistin may be used.

For pseudomonal wound infections, acetic acid with concentrations from 0.5% to 5% can be an effective bacteriostatic agent in eliminating the bacteria from the wound. Usually a sterile gauze soaked with acetic acid is placed on the wound after irrigation with normal saline. Dressing would be done once per day. Pseudomonas is usually eliminated in 90% of the cases after 10 to 14 days of treatment. [55]

Antibiotic resistance

One of the most worrisome characteristics of P. aeruginosa is its low antibiotic susceptibility, which is attributable to a concerted action of multidrug efflux pumps with chromosomally encoded antibiotic resistance genes (e.g., mexAB, mexXY, etc.) and the low permeability of the bacterial cellular envelopes. [56] In addition to this intrinsic resistance, P. aeruginosa easily develops acquired resistance either by mutation in chromosomally encoded genes or by the horizontal gene transfer of antibiotic resistance determinants. Development of multidrug resistance by P. aeruginosa isolates requires several different genetic events, including acquisition of different mutations and/or horizontal transfer of antibiotic resistance genes. Hypermutation favours the selection of mutation-driven antibiotic resistance in P. aeruginosa strains producing chronic infections, whereas the clustering of several different antibiotic resistance genes in integrons favors the concerted acquisition of antibiotic resistance determinants. Some recent studies have shown phenotypic resistance associated to biofilm formation or to the emergence of small-colony variants may be important in the response of P. aeruginosa populations to antibiotics treatment. [40]

Mechanisms underlying antibiotic resistance have been found to include production of antibiotic-degrading or antibiotic-inactivating enzymes, outer membrane proteins to evict the antibiotics and mutations to change antibiotic targets. Presence of antibiotic-degrading enzymes such as extended-spectrum β-lactamases like PER-1, PER-2, VEB-1, AmpC cephalosporinases, carbapenemases like serine oxacillinases, metallo-b-lactamases, OXA-type carbapenemases, aminoglycoside-modifying enzymes, among others have been reported. P. aeruginosa can also modify the targets of antibiotic action, for example methylation of 16S rRNA to prevent aminoglycoside binding and modification of DNA, or topoisomerase to protect it from the action of quinolones. P. aeruginosa has also been reported to possess multidrug efflux pumps like AdeABC and AdeDE efflux systems that confer resistance against a number of antibiotic classes. An important factor found to be associated with antibiotic resistance is the decrease in the virulence capabilities of the resistant strain. Such findings have been reported in the case of rifampicin-resistant and colistin-resistant strains, in which decrease in infective ability, quorum sensing and motility have been documented.

Mutations in DNA gyrase are commonly associated with antibiotic resistance in P. aeruginosa. These mutations, when combined with others, confer high resistance without hindering survival. Additionally, genes involved in cyclic-di-GMP signaling may contribute to resistance. When grown in vitro conditions designed to mimic a cystic fibrosis patient's lungs, these genes mutate repeatedly. [57]

Two small RNA s : Sr0161 and ErsA were shown to interact with mRNA encoding the major porin OprD responsible for the uptake of carbapenem antibiotics into the periplasm. The sRNAs bind to the 5'UTR of oprD causing increase in bacterial resistance to meropenem. Another sRNA: Sr006 was suggested to positively regulate (post-transcriptionally) the expression of PagL, an enzyme responsible for deacylation of lipid A. This reduces the pro-inflammatory property of lipid A. [58] Furthermore, similarly to study in Salmonella [59] Sr006 regulation of PagL expression was suggested to aid in polymyxin B resistance. [58]

Prevention

Probiotic prophylaxis may prevent colonization and delay onset of Pseudomonas infection in an ICU setting. [60] Immunoprophylaxis against Pseudomonas is being investigated. [61] The risk of contracting P. aeruginosa can be reduced by avoiding pools, hot tubs, and other bodies of standing water; regularly disinfecting and/or replacing equipment that regularly encounters moisture (such as contact lens equipment and solutions); and washing one's hands often (which is protective against many other pathogens as well). However, even the best hygiene practices cannot totally protect an individual against P. aeruginosa, given how common P. aeruginosa is in the environment. [62]

Experimental therapies

Phage therapy against P. aeruginosa has been investigated as a possible effective treatment, which can be combined with antibiotics, has no contraindications and minimal adverse effects. Phages are produced as sterile liquid, suitable for intake, applications etc. [63] Phage therapy against ear infections caused by P. aeruginosa was reported in the journal Clinical Otolaryngology in August 2009. [64]

Research

Last 2013, João Xavier described an experiment in which P. aeruginosa, when subjected to repeated rounds of conditions in which it needed to swarm to acquire food, developed the ability to "hyperswarm" at speeds 25% faster than baseline organisms, by developing multiple flagella, whereas the baseline organism has a single flagellum. [65] This result was notable in the field of experimental evolution in that it was highly repeatable. [66]

P. aeruginosa has been studied for use in bioremediation and use in processing polyethylene in municipal solid waste. [67]

See also

Related Research Articles

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<i>Pseudomonas</i> genus of bacteria

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The Pseudomonadaceae are family of bacteria which includes the genera Azomonas, Azomonotrichon, Azorhizophilus, Azotobacter, Cellvibrio, Mesophilobacter, Pseudomonas, Rhizobacter, Rugamonas, and Serpens. The family Azotobacteriaceae was recently reclassified into this family.

Tobramycin chemical compound

Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius that is used to treat various types of bacterial infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.

<i>Burkholderia cepacia</i> complex species of bacterium

Burkholderia cepacia complex (BCC), or simply Burkholderia cepacia, is a group of catalase-producing, lactose-nonfermenting, Gram-negative bacteria composed of at least 20 different species, including B. cepacia, B. multivorans, B. cenocepacia, B. vietnamiensis, B. stabilis, B. ambifaria, B. dolosa, B. anthina, B. pyrrocinia and B. ubonensis. B. cepacia is an opportunistic human pathogen that most often causes pneumonia in immunocompromised individuals with underlying lung disease. Patients with sickle-cell haemoglobinopathies are also at risk. The species also attacks young onion and tobacco plants, as well as displaying a remarkable ability to digest oil.

<i>Stenotrophomonas maltophilia</i> species of bacterium

Stenotrophomonas maltophilia is an aerobic, nonfermentative, Gram-negative bacterium. It is an uncommon bacterium and human infection is difficult to treat. Initially classified as Bacterium bookeri, then renamed Pseudomonas maltophilia, S. maltophilia was also grouped in the genus Xanthomonas before eventually becoming the type species of the genus Stenotrophomonas in 1993.

Phenazine chemical compound

Phenazine is an organic compound with the formula (C6H4)2N2. It is a dibenzo annulated pyrazine, and the parent substance of many dyestuffs, such as the toluylene red, indulines, and safranines (and the closely related eurhodines). Phenazine crystallizes in yellow needles, which are only sparingly soluble in alcohol. Sulfuric acid dissolves it, forming a deep-red solution.

Burkholderia cenocepacia is a species of Gram-negative bacteria that is common in the environment, can form a biofilm with itself, is resistant to many antibiotics and may cause disease in plants.

RyhB

RyhB RNA is a 90 nucleotide RNA that down-regulates a set of iron-storage and iron-using proteins when iron is limiting; it is itself negatively regulated by the ferric uptake repressor protein, Fur.

Swarming motility rapid and coordinated translocation of a bacterial population across solid or semi-solid surfaces

Swarming motility is a rapid and coordinated translocation of a bacterial population across solid or semi-solid surfaces, and is an example of bacterial multicellularity and swarm behaviour. Swarming motility was first reported by Jorgen Henrichsen and has been mostly studied in genus Serratia, Salmonella, Aeromonas, Bacillus, Yersinia, Pseudomonas, Proteus, Vibrio and Escherichia.

Pseudomon-1 RNA motif

The Pseudomon-1 RNA motif is a conserved RNA identified by bioinformatics. It is used by most species whose genomes have been sequenced and that are classified within the genus Pseudomonas, and is also present in Azotobacter vinelandii, a closely related species. It is presumed to function as a non-coding RNA. Pseudomon-1 RNAs consistently have a downstream rho-independent transcription terminator.

CFTR inhibitory factor

The CFTR inhibitory factor (Cif) is a protein virulence factor secreted by the Gram-negative bacteria Pseudomonas aeruginosa and Acinetobacter nosocomialis. Discovered at Dartmouth Medical School, Cif is able to alter the trafficking of select ABC transporters in eukaryotic epithelial cells, such as the cystic fibrosis transmembrane conductance regulator (CFTR), and P-glycoprotein by interfering with the host deubiquitinating machinery. By promoting the ubiquitin-mediated degradation of CFTR, Cif is able to phenocopy cystic fibrosis at the cellular level. The cif gene is transcribed as part of a 3 gene operon, whose expression is negatively regulated by CifR, a TetR family repressor.

Crc (protein)

The Catabolite repression control (Crc) protein participates in suppressing expression of several genes involved in utilization of carbon sources in Pseudomonas bacteria. Presence of organic acids triggers activation of Crc and in conjunction with the Hfq protein genes that metabolize a given carbon source are downregulated until another more favorable carbon source is depleted. Crc-mediated regulation impact processes such as biofilm formation, virulence and antibiotic susceptibility.

ESKAPE is an acronym encompassing the names of six bacterial pathogens commonly associated with antimicrobial resistance: ESKAPE is an acronym for their names and a reference to their ability to escape the effects of commonly used antibiotics through evolutionarily developed mechanisms, and also because it is a acronym made from the first letters of their scientific names:

Twitching motility is a form of crawling bacterial motility used to move over surfaces. Twitching is mediated by the activity of hair-like filaments called type IV pili which extend from the cell's exterior, bind to surrounding solid substrates and retract, pulling the cell forwards in a manner similar to the action of a grappling hook. The name twitching motility is derived from the characteristic jerky and irregular motions of individual cells when viewed under the microscope. It has been observed in many bacterial species, but is most well studied in Pseudomonas aeruginosa, Neisseria gonorrhoeae and Myxococcus xanthus. Active movement mediated by the twitching system has been shown to be an important component of the pathogenic mechanisms of several species.

SrbA is a small regulatory non-coding RNA identified in pathogenic Pseudomonas aeruginosa. It is important for biofilm formation and pathogenicity. Bacterial strain with deleted SrbA had reduced biofilm mass. As the ability to form biofilms can contribute to the ability a pathogen to thrive within the host, the C. elegans hosts infected with the srbA deleted strain displayed significantly lower mortality rate than the wild-type strain. However, the deletion of srbA had no effect on growth or antibiotic resistance in P. aeruginosa.

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