The study of cystic fibrosis (CF) is an ongoing and developing area. the objective of this SSM was to study bacterial infections in CF, and summaries the methods used in diagnosis and treatment of CF. An evaluation of the current problems that need to be addressed concerning CF clinics was also made.
Relevant articles were accessed using various sources including online databases and hand searching archives in Harold Cohen Library.
Information was gathered about the various bacteria that cause infection in CF sufferers, being Pseudomonas aeruginosa and Burkholderia cepacia complex. CF treatments, such as antibiotic therapy, drug therapy and lung transplantation, and their effectiveness was also explored. Focus was also placed on major epidemic strains, such as LES and ET12.
The conclusions drawn from the study concerned the issues facing CF clinics around the country and the problems of antibiotic resistance were also noted, with progressions that could be made to improve the situation in the future.
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Further recommendations were suggested for future CF studies and the limitations experienced during this paper were stated.
"Cystic Fibrosis (CF) is an autosomal recessive genetic disorder, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on the long arm of the seventh chromosome"1. The CFTR gene encodes a protein in the cell membrane of cells, which is involved in the transport of chloride ions in and out of the cell2. There have been over 1000 mutations identified in the CFTR gene to cause CF3; most commonly these are either the substitutions of amino acids in the gene, or the deletion of parts of the DNA3. The most common mutation, occurring in around 60% of sufferers1, is the deletion of an amino acid at position 508 on the CFTR gene, called delta F5081, 3.
The effects of this mutation are numerous throughout the human body, and affect multiple systems, including respiratory, gastrointestinal, and reproductive. The mutation of the CFTR gene leads to thick, sticky, viscous mucus secreted by the glands in the airways and pancreas of sufferers. Normally, ciliated epithelial cells line the trachea and primary bronchi, which form an escalator, sweeping any mucus and foreign particles up the trachea and into the oropharynx where it is usually swallowed4. In individuals with CF, however, the thick mucus secreted interferes with the cilia escalatory and renders it ineffective. This, then, leads to accumulation of large amounts of thick mucus in the airways, which cannot be cleared. It is these mucus surfaces that become the breeding ground for colonising bacteria in case of infection.
Several methods were used to search for information and articles for this SSM.
Books were accessed and checked out from the Harold Cohen Library for reading, and a hand search for articles was carried out. This though wasn't very useful, as many of the articles were outdated and not relevant to current research.
Majority of the articles were accessed using search engine databases such as Ovid, Pubmed and Science direct. These databases were used to search for the articles from journals online. The BMJ website was also accessed to retrieve articles of relevance.
Human only studies
English language only
Randomized Control Trials
There were many searches made on each database. The limits used on each were:
Also MeSH terms were also used in the Medline database; this helped to retrieve as many relevant articles as possible for the subject area.
Here is an example of one search used in the Ovid database, and how searches were narrowed down to relevant articles.
Number of articles returned
Pseudomonas aeruginosa AND Cystic fibrosis
UK cystic fibrosis clinics
Limits used were: Human only studies, English text, Full text
Pseudomonas aeruginosa AND cystic fibrosis AND UK cystic fibrosis clinics
Key Bacterial Infections Concerned with CF
Individuals with CF are more susceptible to bacterial infections from organisms such as Pseudomonas aeruginosa, due to dehydration in the airways leading to formation of thick mucus5, 6.
There are many bacteria known to cause infection in patients with CF including the Burkholderia cepacia complex7, Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae1.
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In early childhood, the incidence of infection with Staphylococcus aureus and Haemophilus influenzae are much more common while later in life, the incidence rates of infection with Ps. aeruginosa and the Burkholderia cepacia complex is more of a problem1.
Ps. aeruginosa is "a Gram-negative, rod shaped bacillusâ€¦ It is motile, usually due to one or two polar flagella"8. It is primarily an aerobe, but can also grow anaerobically in the presence of nitrate to act as a terminal electron acceptor8.
Ps. aeruginosa is usually found on moist surfaces, such as sinks, the floors of showers, and in soil. It is an opportunistic pathogen, so infects areas where the defence is already breached, such as wounds in burns victims. Usual symptoms are sepsis and inflammation.
Ps. aeruginosa is the most common pathogen associated with the infection of the lungs of CF sufferers, with the highest rates of morbidity and mortality9. Once the Ps. aeruginosa is flourishing in the lungs, it is difficult to eradicate even after the most intensive antibiotic treatment9, 10and leads to chronic lung disease9.
The incidence of Ps. aeruginosa infection in the Adult CF Centre, Broadgreen Hospital, Liverpool, is around 80%, with 50% of those being infected with the 'Liverpool Epidemic Strain' or 'LES'.
Ps. aeruginosa, was thought to infect mostly in adults, but recently studies have shown that there is increasing prevalence in children, with 97.5% of children being found to have been infected by the age of three, in centres in the US, identified by culture and serologic results1, 11.
Once Ps. aeruginosa are colonised in the lungs of CF patients, they are difficult to eliminate. This is due to the bacteria forming biofilms, creating a barrier to antimicrobial agents, such as antibiotics and antibodies.
The lungs of CF sufferers are infected by non-mucoid strains of Ps. aeruginosa, which are followed by the emergence of the mucoid variants8. These produce a thick mucoid (a capsule like polysaccharide) which acts as a barrier against phagocytic cells of the body.
These mucoid strains lead to chronic debilitating pulmonary function, which lead to large numbers of neutrophils being attracted to the place of infection. This therefore causes inflammation in the lungs of the sufferers, leading to inflammatory exacerbations; it is these exacerbations that usually lead to hospitalisation, and Intra-Venous antibiotic administration.
CF sufferers are usually infected with their own unique strain of Ps. aeruginosa, but recently there has been emergence of several 'epidemic strains' such as the Liverpool epidemic strain (LES), which once in the lungs replaces the hosts' strain. Hence, the LES is more transmissible between patients, leading to greater complications concerning segregation and infection.
Burkholderia cepacia complex
Burkholderia cepacia was first discovered in mid 1940's, in New York, where vegetable growers became infected. The four bacterial isolates discovered were given the name 'cepacia' which means 'of onion'.
They are gram-negative bacteria, which are rod shaped with polar flagella, making them motile.
At the time, it was thought to be in the Pseudomonas genus, but was reclassified in the early 1990's to the new genus Burkholderia. At the moment there are ten known genomovars of the Burkholderia cepacia complex12.
According to current research, B. cenocepacia is the most common strain causing infection in CF patients13, with a mean of 67.5% of infected patients in three CF clinics in the USA, Canada and Italy13. The next most common is B. multivorans13 with a percentage prevalence of 17.3% in the same CF clinics.
There are strains of Burkholderia cepacia that are highly transmissible including the ET-12 strain. The ET-12 strain is a strain of the genomovar III of the Burkholderia cepacia complex.
Respiratory secretions can spread it easily, for example, by kissing1. This creates a problem for clinicians, as the ET-12 strain can 'super-infect' patients, replacing their own unique non- epidemic strain1. This can result in cepacia syndrome, which is fatal. Clinicians should therefore be careful about segregating these patients so as not to spread these epidemic strains.
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Burkholderia cepacia produces a wide variety of cytotoxins, lipase, protease, haemolysins and mucin sulphatase1. These are what the bacteria use to attack the cells in the CF airway1. The haemolysins are of importance, as they are linked to the programmed cell death of neutrophils1, 14. This protects the bacteria from immune responses causing lung damage1. The cytotoxins produced by the Burkholderia cepacia complex also promote macrophage and mast cell death1; they also cause the macrophages to release oxidants, which lead to chronic inflammation1, which lead to exacerbations and hospitalisation.
Prevention and treatment of infections
In childhood the priority of CF clinics is to keep the child healthy and to delay the onset of bacterial infection. This is done by keep the child active, well- fed and free of infection as a healthy child has a better chance of fighting off an infection.
Methods of Prevention Include:
A course of antistaphylococcal antibiotics is currently diagnosed for newborns at all times to prevent infection of staphylococcus aureus. If infection occurs, a further course is given to try and eradicate it.
This is a controversial method of prevention; there have been few studies that indicate that the longer the child stays free of Staphylococcus aureus the more likely it is to get infected by Ps. aeruginosa1, 15. The current problem is that there have not been many studies carried out showing that Ps. aeruginosa infection is accelerated by use of antistaphylococcal drugs.
This is due to several reasons. Firstly, ethical considerations must be taken into account as it is considered unethical to withhold antibiotics from a child. Also, the study would have to be carried out using many participants across several countries, which would take lots of time and would be costly.
Methods of Treatment Include:
There are several ways of administering antibiotics to CF sufferers, depending on their needs. Inhaled antibiotics are given for months, to increase pulmonary function and reduce bacterial colonisation. Oral antibiotics are given to prevent bacterial infection, and intravenous antibiotics given when a patient is infected with bacteria.
Different types of antibiotics are used in the treatment of an infection, and usually two courses given to run alongside each other, with each antibiotic being a different type, which attacks bacteria in a different way, for example, tobramycin prevents the formation of 70S ribosomes16, whereas ciprofloxacin inhibits cell division16.
Common antibiotics used to treat Ps. aeruginosa and B. cepacia complex infections are: tobramycin, ciprofloxacin, ceftazidimide, piperacillin, meropenem, colistin, doxycycline and chloramphenicol16.
The antibiotics are chosen depending on the bacterial susceptibility; sputum samples are taken from the CF patient, the bacteria present in the sample are cultured on a disc with antibiotic discs. The area of clearance around the discs indicated the bacterial susceptibility to the antibiotic. If there is no area of clearance around the disc, the bacteria are resistant to that particular antibiotic.
Lung transplantation is the most aggressive form of treatment of CF17, and is used when all other treatments have failed. Chronic pulmonary lung disease is the cause of 80% of deaths related to CF17; the lung transplantation aims to cure this, and has two main goals. The primary goal is to treat the end-stage lung disease, and the secondary aim is to improve the sufferer's quality of life17.
The survival rate of the lung transplant is variable for each individual, there are survival models, which can predict whether a patient will have an increase or decrease in survival17. But there are no models that can justify whether the survival rate is justified by the quality of life17. Even though quality of life decreases as length of time since the transplant, it is usually justified for patients with end stage lung diseases.
Discriminating between different bacteria and strains.
Identifying different strains of bacteria is essential for diagnosis of infections so that treatments can be carried out. Identification of different strains can also give information about the rate of infection spread, and if there are epidemic strains.
This method is used to discriminate between organisms of the same biotype. A biotype is a group of organisms with the same genotype. This is done by staining the bacteria. It can give a quick and accurate identification if a patient is Ps. aeruginosa positive or not. It cannot distinguish between different strains of the same genotype, for example, between different strains of Ps. aeruginosa. It may be unstable because of loss of property.
Serotyping is used to identify the organisms into serotypes, depending on the surface structures of the bacteria. The method uses antisera, to test the antigen- antibody reactions. The problems though are that it fails to identify non-motile strains18. Also for some species, conservation of antigen epitopes renders Serotyping of little value.
Restriction endonuclease typing
Restriction enzymes are used to cut DNA at a specific sequence recognition site, this produces many small fragments of DNA, which can then be run through a pulsed- field gel electrophoresis. The larger fragments of DNA move through the gel slower than the shorter fragments, so at the end a DNA 'fingerprint' is obtained, which can then identify the bacteria present. It can identify variations in strains of bacteria, which makes it accurate.
Polymerase chain reaction typing (PCR)
PCR is a technique which allows specific sequences of DNA to be amplified. The method involves heating DNA strands to different temperatures with specific heat resistant DNA polymerase and base primers. PCR can create many strands of DNA in a relatively short space of time; many labs are now starting to use this method as it is very accurate, and takes little time.
There are different ways of identifying each, with advantages and disadvantages:
Information for this table taken from David Greenwood RCBS, John F. Peutherer. Medical Microbiology: A guide to Microbial Infections: Pathogenesis, Immunity, Laboratory Diagnosis and Control. Sixteenth ed: Churchill Livingstone; 2002.8
The Liverpool Epidemic Strain (LES)
LES is an example of an epidemic strain of Ps. aeruginosa; there are other epidemic strains, such as Manchester, Jones et al 200119. Chang et al first reported LES in 1996, where it was found that a transmissible, drug resistant strain of Ps. aeruginosa was spreading amongst patients20, in Liverpool Adult CF centre. The epidemic strain replaces the existing unique strain in the CF sufferer, providing a problem for clinicians, because spread needs to be managed.
LES is the most prevalent epidemic strain in England, with it being present in 11% of patient isolates in England and Wales19. In the Liverpool Adult CF unit, 50% of Ps. aeruginosa positive patients are LES positive. There is a greater morbidity associated with patients colonised with LES, rather than a non-epidemic strain20, so controlling the spread is of paramount importance.
In CF centres such as at Broadgreen, the main method of controlling the spread of LES is by segregation of the LES positive patients. Having clinics on different days for LES positive and negative patients reduces the contact that non-LES patients have with the strain. This reduces the airborne spread of LES, which has been shown to account for much of the patient-to-patient spread of the bacteria21. Regular sputum samples are taken from the patients and analysed, testing for Ps. aeruginosa and in particular LES, these samples are taken every 3-6months.
Clinical decisions based on bacterial tests.
There are many clinical decisions based on the bacterial tests carried out on the samples. The samples identify the bacteria and which strains are present. This information is then used as a basis for the segregation of patients, patients with B. cepacia complex segregated from those with Ps. Aeruginosa, and both being segregated from bacteria- free patients. This is an important procedure, as it reduces the spread of bacteria within the CF centre and cross- infection between patients.
Different antibiotics are administered to the patients depending on the results of the antibiotic sensitivity charts. The antibiotic sensitivity charts indicate to the clinician whether a strain of bacteria causing infection in a patient is susceptible to a certain antibiotic. The clinician can then consider these results when administering antibiotics to a patient.
On many occasions, however, the results of the antibiotic sensitivity tests are not taken into account by the clinician. This is due to the time taken for the results of the sensitivity tests to be published as the clinician may have to administer antibiotics immediately. In this case, the clinician usually takes into account the patients past experiences with antibiotics. If they found one antibiotic particularly effective against an infection in the past, that antibiotic would be administered again.
The problems associated with this approach to administering antibiotics include that the patient may later come back as 'resistant.' Hence, the administration of that antibiotic could increase the problem of resistance in the bacterial population. Also, if the clinicians are not using the antibiotic sensitivity charts, the analysis of bacterial samples is a waste of resources as that time and money could be used more beneficially elsewhere.
The Primary Issues facing CF Clinics
One of the main issues surrounding CF Clinics is the chance of cross- infection. This is reduced by segregating patients based on the bacteria they are infected with, for example B. cepacia complex positive patients are segregated from all other patients, and also Ps. aeruginosa positive patients are segregated.
The second problem is then associated with the segregation of patients as the CF centre may not have the space to be able to segregate the patients adequately based on their infections. As mentioned previously, there are over ten know genomovars of B. cepacia complex. In an ideal situation, patients with different genomovars would be segregated from each other, due to the fact that some infections, such as B. cenocepacia and B. multivorans, have a higher morbidity rate. However, this practise is rarely carried out as centres do not have the space or resources to isolate patients based solely upon the strain they are infected with. There is also the problem of isolating the patients that are infected with epidemic strains with a high transmissibility, such as LES or ET12.
Segregation, though, has been controversial and unpopular with CF patients22. Furthermore, the strict segregation does not prevent patients from being infected by the bacteria from the environment23.
Despite recommendations favouring segregation, by the UK CF Trust Infection Control Group24, little is known about the emotional and psychosocial effects on patients, particularly children24. There have been conflicting studies, supporting both sides of the argument. According to Duncan M Geddes25 the isolation of patients with different strains of bacteria may yield little benefit. Also there is the issue of stigmatisation of the individuals, leading to increased anxiety on the patients and their families25. Contrary to this, research carried out by Russo et al24 shows that 91% of patients support the segregation of patients, viewing it as necessary for the well being of their children. It was also found that the majority of the children were in favour of the segregation as they understood the health risks. A criticism concerning this study is the worry expressed by children and parents concerning the boredom of the isolation, which could add extra anxiety, uncertainty and stress to the patient24.
Due to the variation in opinion on this subject, it is difficult to establish whether segregation is a positive or negative solution. It should be noted, however, that cross- patient infection rates would decline if resources permitted segregation of patients with transmissible strains of bacteria.
Another issue facing CF clinics is the discovery of new strains of bacteria, particularly epidemic and transmissible strains. When a sputum sample is taken from a patient, it is cultured and tested for known strains of bacteria. The problem with this method is the difficulty involved in identifying new strains unless consciously looking for them, using accurate typing. Usually CF clinics don't scan for these new strains, as the discovery of a new transmissible strain will result in complications, and implementation of new guidelines to deal with it. When LES was discovered in 1996, the Liverpool Adult CF clinic had to implement new guidelines, involving segregation, patient contact and antibiotic use which was costly and took time. If these new strains aren't looked for though, the new epidemic strains may spread between patients quickly and even between CF clinics, as with LES.
Finally, there is also the question of educating CF sufferers and patients. CF sufferers are usually well educated by the clinic and their knowledge on bacteria and infections is substantial. This needs to be sustained in the future, as education of patients plays an important role in eliminating infection. Patients need to know how to remain infection- free. It is also important for children to stay healthy and exercise regularly.
Recommendation for Further Studies:
Currently there is a steady increase in the life expectancy of patients diagnosed with CF. In order to maintain this trend, a number of changes need to be implemented.
There are a set of guidelines that each CF centre follows. In general, these guidelines are followed by the centres across the UK, but there are some differences in the treatment of the patients involving patient segregation, administration of drugs, or testing of sputum samples.
If all CF centres across the UK were to follow set procedures, then this may lead to a decrease in the antibiotic resistance of certain bacterial strains, and also the infection- rate of epidemic strains.
On a worldwide scale, different countries employ different methods in dealing with CF, which may increase global prevalence of epidemic strains. In Denmark, they are much more aggressive in fighting infection in young children, by administering high dosages of various types of antibiotics. The UK is more passive with their antibiotic treatment, administering fewer antibiotics, and lower dosages to patients.
There is an increasing problem in dealing with CF in the developing world26. In developing countries, such as India, sputum samples are rarely tested due to the lack of resources available to the clinicians; this means that infection may be able to spread rapidly. The cost of antibiotics to the sufferer is large, and in many cases cannot be afforded, leading to higher prevalence of bacteria such as Ps. aeruginosa and B. cepacia complex. There is also a problem with malnutrition in these countries, and children diagnosed with CF are often unhealthy and already infected with Ps. aeruginosa26 due to lack of diagnosis techniques, such as the sweat diagnosis26. There is also a problem with infection; children have a frequency of more than four episodes of pneumonia per year26.
Due to the increasing number of antibiotic- resistant strains of bacteria, more research on the manufacture of improved antibiotics needs to be carried out. The problem is exacerbated in transmissible and epidemic strains, such as ET12 and LES, which increases the spread of infection.
Currently at Alder Hey Children's Hospital when a newborn is diagnosed with CF, the procedure is to keep the child on one antibiotic at all times, in order to prevent colonisation of bacteria. This method is considered controversial as there have been suggestions that keeping children free from S. aureus can increase the likelihood of the child getting Ps. aeruginosa which, ultimately, is what the CF centre wants to avoid. Also if the child is being administered a great number of antibiotics from an early age, the likelihood that the bacteria will become accustomed to the antibiotics, and hence, resistant is increased.
Limitations Experienced during the Study
The time restraint was very severe due to the sheer number of articles and reviews on this subject. With more time, more research into the subject area could have been carried out.
The word count restriction prevented various issues that were read and could be discussed in the review from being expressed.
Some relevant articles were also not freely available for viewing.
A language limitation was also experienced as the only reading language that could be use was English, making certain articles inaccessible.
There were several limitations on my study:
The average life expectancy of CF sufferers has been steadily rising over the years, and with continued improvements in the care of CF sufferers, this will continue to rise.
The lungs of CF sufferers are particularly prone to bacterial infections, such as Ps. aeruginosa and B. cepacia complex. There are many different strains of Ps. aeruginosa and over 10 known genomovars of B. cepacia complex, all capable of causing infection. There are epidemic and transmissible strains of Ps. aeruginosa and B. cepacia complex, known as LES and ET12, these are particularly dangerous, as they are highly transmissible between patients, and have a high antibiotic resistance.
In childhood, the priority is preventing the CF sufferers from being infected by bacteria, but as age increases, the likelihood of infection also increases, and so different treatments are used. These include physiotherapy, antibiotic therapy and as a most aggressive treatment, lung transplantation. Antibiotic therapy is the most common therapy used, with the majority of CF patients always on at least on e course of antibiotics.
There are several problems facing CF centres, these include the segregation of patients, which is affected by the amount of resources available to the centre. Isolation is one of the main ways of stopping the spread of bacterial infection between patients, and has been controversial, with some studies saying that the detrimental effect on patients mentally.
The research carried out in the subject area could be improved, many of the articles that are accessed are reviews, which give a good basis of knowledge, but are not trials, and the majority of the articles I accessed though were not RCT's, even though I searched for them. Preferably RCT's would be accessed as theses are the best kind of trial. Not many of the trials carried out were multi-central and multi-country. This is due to the fact that it is expensive and time consuming to carry out a trial over several countries. It would also be beneficial to carry out trials on newborns to test whether administration of antibiotics at birth accelerate the onset of Ps. aeruginosa. These trials though would be unethical, and also would have to involve many participants in several countries, over a period of around 20 years.