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A French military surgeon in 1850 was the first to describe an infection with Pseudomonas aeruginosa when he discovered blue pus in the dressings of wounded soldiers.1 The colour resulted from the secretion by the bacterium of its characteristic pigment pyocyanin. By 1984 more than 102 different species were included in the familyPseudomonadaceae, most of which were plant pathogens or soil saprophytes. All are straight or curved Gram negative rods that are motile by polar flagella. Most are strictly aerobic, can grow in temperatures from 4–43°C and are usually oxidase positive. Application of DNA technologies to microbial taxonomy has led to further divisions within thePseudomonadaceae. This has resulted in a proliferation of “new” genera and species much to the consternation of clinicians and clinical microbiologists alike.
The taxonomic tool used most frequently is analysis of 16S and 23S ribosomal RNA (rRNA) cistrons. These regions are relatively well conserved. For example, it is estimated that the average substitution (mutation) rate for 16S rRNA within a particular eubacterium is 1% per 50 million years.2 However, there is sufficient variability to permit delineation of genera and species. This analysis can be done by DNA/DNA hybridisation but is currently most often achieved by polymerase chain reaction (PCR) amplification of a large portion of the 16S rRNA gene and sequencing the amplicon;Pseudomonadaceae have thus been split into five rRNA groups (table 1).
rRNA group I
The most important human pathogen in this group isP aeruginosa. It has a ubiquitous distribution in the environment and can adapt to living and multiplying in such unpromising habitats as distilled water and disinfectants. Sinks, taps, and drains in hospitals are always colonised but these isolates seem rarely to infect patients. It is not normally part of the skin, pharyngeal or intestinal flora. It will however colonise waterlogged skin, and can produce folliculitis and otitis externa. It is also a common cause of infections in burns, which can lead to septicaemia and death. P aeruginosa can produce keratitis, corneal ulceration, which may progress to endophthalmitis, and orbital cellulitis. The most common sources for such infections are contact lens fluids and ocular medication.3
P aeruginosa is an important cause of meningitis in neonates and of septicaemia in neonates and immune compromised children.4 5 It is also a cause of urinary tract infection in children with anatomic or functional abnormalities of the bladder. But it is in children with cystic fibrosis (CF) thatP aeruginosa is most frequently encountered.6 Up to 90% of patients in CF clinics are colonised or infected with P aeruginosa. Colonisation rates increase with age and are associated with an increased decline in lung function.6 Application of methods of genomic analysis such as pulsed field gel electrophoresis (PFGE) of macrorestricted chromosomal DNA, flagellin gene polymorphisms, or arbitrarily primed PCR (AP-PCR) have shown that epidemic strains of P aeruginosa can spread among patients attending the same CF clinic.7 8
P aeruginosa can produce a vast array of virulence determinants including adherence factors (pili), flagella (for motility), extracellular polysaccharides (alginate in mucoid isolates), proteases, (such as elastase), cytotoxins (leucocidin), and exotoxins. The exotoxins include exotoxin A, (which is closely related to diphtheria toxin and inhibits protein synthesis by ADP ribosylation of elongation factor 2) and exoenzyme S (another ADP ribosyl transferase). Interestingly P aeruginosafrom patients with CF appear to be more often mucoid and non-motile, to have short polysaccharide side chains on their lipopolysaccharide (which render them serum sensitive), and produce fewer secreted proteins.
Our understanding of host–microbe interactions has been revolutionised in the past decade. It is clear that there is extensive biochemical “crosstalk” between bacteria and host cells. Thus the bacteria are influenced by their environment and in turn alter host cell behaviour. This is often mediated by type III secretion systems in Gram negative bacteria.9 10 Such systems are assembled in response to—for example, contact with host cells, and allow ATP powered secretion of unmodified proteins across the bacteria’s two lipid membranes and their injection into host cells. The injected proteins often resemble eukaryotic signal transduction factors capable of stimulating or suppressing host cell intracellular messages. The genes for type III secretion systems are clustered together on the bacterial chromosome (with or without the secreted protein genes) and appear to be well conserved between a range of plant and animal pathogens. They have a different G + C% molar ratio from the rest of the bacterial chromosome and appear to have been acquired laterally during the evolution of pathogenicity.9 10 They have been termed pathogenicity islands10 and have been found in human pathogens such as Escherichia coli, Salmonellae, Shigellae, Chlamydia trachomatis, Bordetella pertussis, andYersinia enterocolitica. Recently a type III secretion system has been found in P aeruginosa, which secretes exoenzyme S and other proteins related to Yersinia spp Yop B and D.11 Interestingly, mutant P aeruginosa that were able to invade epithelial cells, were shown to have defects in this type III secretion system, were no longer cytotoxic, and did not secrete the Yop B and D homologues.12
rRNA group II
Burkholderia cepacia is an increasingly important opportunist pathogen, especially in CF and chronic granulomatous disease.6 13 In CF, acquisition ofB cepacia can be associated with rapidly declining lung function and death: the cepacia syndrome.6 14 Although B cepacia is highly prevalent in the environment, some strains have an enhanced capacity to spread from patient to patient and cause disease.6 13 A highly transmissible strain ofB cepacia is ET12 (Edinburgh–Toronto electrophoretic type 12), which has spread to over half the CF clinics in the UK.15 ET12 expresses long intertwined cable pili and it, and other highly transmissible strains, all contain a novel DNA sequence (1.4 kb) “BCEM” (B cepaciaepidemic strain marker), which is related to transcriptional regulators in other bacteria.16 A number of techniques are available to type B cepacia isolates including PFGE, ribotyping, AP-PCR, and flagellin gene polymorphisms.6 14 16 17 It is now clear that allB cepacia strains are not the same and that colonisation with a low virulence strain does not prevent subsequent colonisation, infection, and death from more virulent ET12.14 This of course poses further problems for control policies aimed at preventing acquisition of B cepacia by patients with CF.18
Virulence factors of B cepacia are not completely defined but include attachment factors,15flagella,17 and extracellular enzymes.6 In mucous membranes where there is heavy bacterial colonisation, the mucin polysaccharide is sulphated, which is the case in the mucin from patients with CF.19 It is thought that sulphation protects mucin from degradation by bacterial glycosides.20 We have recently shown that some strains of B cepacia and, to a lesser extent, P aeruginosa have mucin sulphatase activity.21 Such activity might not only aid degradation of mucin but also expose new receptors for the bacteria.
B mallei and B pseudomallei cause glanders and meliodosis, respectively.B mallei is primarily an equine pathogen and a rare zoonotic pathogen. B pseudomalleicauses meliodosis, an acute and chronic infection of man and other animals, and is endemic in South East Asia, Northern Australia and Papua New Guinea. However, it is present in soil in many other parts of the world, and infection is thought to be acquired through soil contamination of skin wounds, by ingestion or inhalation. It causes septicaemia, pneumonia, osteomyelitis, and soft tissue (including brain) abscesses. It appears the bacterium can remain dormant, presumably in macrophages, to re-emerge years later. It is sometimes referred to as the “Vietnamese time bomb” as it is currently producing infection in US veterans of the Vietnamese war. It can be very difficult to treat and results in high mortality. We know little about its pathogenesis; however, a complex of genes encoding a type III section system has been found recently on the replicons ofB pseudomallei.22 In addition, exotoxins including cytotoxic glycolipids have been implicated in melioidosis.23 24
Oxalobacter formigenes is part of the normal enteric flora and breaks down oxalate to CO2 and formate. In children with CF, carriage of O formigenes is rare (only 16% of subjects), and over half of those not colonised are hyperoxaluric.25 It is conceivable that this is related to the increased risk of calcium oxalate urolithiasis in patients with CF.
Other rRNA groups
Each of the remaining bacteria is an opportunist pathogen.Stenotrophomonas maltophilia has changed names twice, from Pseudomonas toXanthomonas then to its final designation. On nutrient agar it produces yellow colonies, (hence the previousXanthomonas). It is widely distributed in the animate and inanimate environments, and can cause life threatening bacteraemia, endocarditis, and pneumonia. It is associated with respiratory tract infection in patients with CF, generally late in the disease process. It is usually resistant to imipenem by expression of a carbapenemase, but most isolates are sensitive to ceftazidime, cefotaxime, cotrimoxazole or ticarcillin/clavulanate. There are many clinically useful combinations of cotrimoxazole and other agents in treating S maltophiliainfection.26
Although this represents the current taxonomic status of thePseudomonadaceae, there will undoubtedly be further changes. For example, there are currently further divisions ofB cepacia into genomovars27 and movement of some isolates to different species.28
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