Difficult To Treat Microbes

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Contents:

  • About Bacterial Resistance to Antibiotics
  • Help in Fighting Resistant Bacteria
  • Definition of B. Cepacia (aka Pseudomonas cepacia)
  • Methicillin-Resistant Staphylococcus Aureus (MRSA)
  • Stenotrophomonas maltophilia (10/97)
  • Aspergillosis
  • About Bacterial Resistance to Antibiotics

    Apparently most antibiotics are derived from natural sources or modeled after them. This means that resistance factors already exist in nature. In addition to chromosomes, which allow the bacteria to replicate themselves, they also have ring shaped strands of functioning genetic material called plasmids. These plasmids generate proteins which can produce resistant effects to antibiotics. The kicker is that bacteria can exchange plasmids and thus resistance factors. Even different types of bacteria can exchange plasmids. Transpons are short pieces of DNA which can exchange material between chromosomes or between plasmids and chromosomes allowing resistance factors to be incorporated in a bacteria’s genes.

    The human body harbors thousands of different types of bacteria without being affected. Pseudomonas aeruginosa is commonly found on skin! We have, and even require, a constant colony of bacteria. An example is escherichia coli in our intestines. When we take a course of antibiotics, if some e. coli have resistance they will be naturally selected and displace e. coli without resistance. This will increase the amount of resistance factors in our body and increase the probability that the resistance factor is transferred to a pathogenic or disease causing bacteria when it comes along.

    Some bacteria, as is the case with Burkholderia Cepacia (B. cepacia, formerly known as Pseudomonas cepacia), are multiply resistant or resistant to more than one type of antibiotic. Over use or inappropriate use of antibiotic can increase the number of resistance factors in our environment. A good example is that the U.S. is one of the few countries which allow the use of antibiotics in cattle. Other countries outlaw the use of human antibiotics in animals. Apparently it has been documented that resistance factors cultivated in cows by the use of routine antibiotics have been transferred not only to the ranchers family but also the nearby community.

    Apparently low doses of antibiotics for extended periods promotes the generation of resistant strains of bacteria. The full course of antibiotics prescribed is chosen to maximize the destruction of the targeted pathogen and minimize the generation of resistance factors. There is an ongoing race between the sea of genetic material available to bacteria and the antibiotics being discovered and adapted by people.

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    Help in Fighting Resistant Bacteria

    Columbia College of Physicians and Surgeons (Columbia Medical School) in New York has a screening program for multi-resistant bacteria. If I understand the procedure correctly, your doctor either calls them with the result of your sputum culture, or sends a sample of sputum to Columbia for growth in their labs. They put it through a series of sensitivity tests using single and multiple drugs, to test not just sensitivity to the individual drugs but also to look for the most effecient paring of drugs (those that would act synergistically to overcome resistance). The report they give back is quite detailed and give recommendations on various drug(s). They tested some two dozen or so. It takes a couple of weeks to get the results.

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    Definition of B. Cepacia (aka Pseudomonas cepacia)

    Basically, it’s a nasty little drug-resistant bacteria that has widely varied effects on people. Some carry it around for years with no ill effects. Some have very serious, very immediate effects. Most are somewhere in between. Apparently the same type of bacteria can carry different resistance factors. As a result, different people infected with different burkholderia cepacia can experience differences in susceptibility or resistance to antibiotics.

    B. cepacia is quite different from Pseudomonas aeruginosa. First and foremost, innumerable epidemiology studies have been done concerning Pseudomonas aeruginosa. We know that unlike B. cepacia, P. aeruginosa is ubiquitous and found nearly everywhere in the environment from water sources to soil. This means it is difficult to avoid and sooner or later people with CF will harbor P. aeruginosa. Whereas B. cepacia is rarely found in the environment and the means of cross-infection appear to be via person-to-person transmission.

    Reducing the Risk of Infection by B. Cepacia

    From: Annals of Internal Medicine (May 15 issue, p.762-766). Hamill and his colleagues in Texas reported on the hospital transmission of Burkholderia cepacia. They reported an epidemic of B. cepacia transmission during 7 months in 1990-91 in which 47 patients became infected with B. cepacia shortly following admission to the hospital (average stay before infection was 2 days). To fully appreciate the following story it helps to remind yourself that B. cepacia can live in plain water.

    An epidemiologist compared these 47 cases to 135 patient controls. Evaluation of a third of the controls showed no evidence of B. cepacia infection. Cases and controls did not differ on any demographic measures such as age, ethnicity, nature of illness, number of days in hospital, number of days in intensive care, steroid, antacid therapy.

    Cases and controls *did* differ, however on the following measures:

  1. number of days on the ventilator
  2. receiving nebulized albuterol treatments
  3. receiving beta-lactam, aztreonam, or macrolide-vancomycin antibiotics

The authors concluded that the outbreak was related to respiratory therapy practices. They observed that the respiratory therapists failed to adhere to accepted infection control practices. Specifically:

  1. Respiratory therapists commonly cross-covered all 3 intensive care units simultaneously, when staffing was low.
  2. When administering treatments, they carried a 10 ml bottle of albuterol in their pockets, sometimes for days at a time, and used it for multiple patients.
  3. Hand washing was not regularly done.
  4. When patients were weaned from ventilators, the in-line nebulizer remained attached to the tubing and was frequently observed to be moist from condensation.
  5. In-line nebulizers were not routinely removed from the tubing, rinsed or dried between treatments.

Personnel from the intensive care unit were convened to deal with this outbreak. Certain control measures (listed below) were instituted. Immediately after institution of these control measures, three additional cases of B. cepacia were identified. In the subsequent 46 months, no additional cases were identified.

Here’s the important message: The control measures taken to prevent transmission of B. cepacia were the following:

  1. Infected or colonized patients were confined to designated areas of the intensive care units.
  2. Meticulous attention to hand-washing, aseptic technique, and medication dispensing practices was enforced.
  3. Dedicated (separate) bottles of albuterol were supplied to individual patients.
  4. At the end of each nebulizer treatment, the residual contents were discarded and the cups were washed, rinsed in *sterile* water, and *dried before* the next use.

Recommendations

In my experience, hospital staff are chronically short-staffed. Hospital staff are tempted to skip steps that might seem to the naive patient to be superfluous. Such “dispensable” steps include washing hands, rinsing the nebulizer with sterile water, not using a nebulizer again until thoroughly dried. These all take time. This is time that could spell the difference between life and death in a patient with cystic fibrosis, however. Although the illnesses of the patients in this study were not identified and did not differ significantly between cases and controls, the B. cepacia patients were 57% more likely to die than the controls. Hospital transmission of deadly bacteria is all too common. If you or your child has to visit a hospital, insist on the control practices listed above.

What we say to any hospital staff, including physicians, about to touch our son is the following: “I am delighted that you plan on examining my son. Before you do, however, I have to ask you to wash your hands in my presence. My son is extremely susceptible to respiratory infections. I can’t allow anybody to touch him who hasn’t thoroughly washed his hands and not touched anything else since.”

When hospital staff wanted to nebulize my son, I first investigated how clean the nebulizers were. When I found out that they were stored in non-sterile bags I insisted on the hospital staff using nebulizers that we had cleaned previously at home. We did not allow them to use the same nebulizer twice, which was their customary practice. They complied with only a little bit of resistance (they called us “fanatics”).

Health psychology (my field) research has consistently shown that assertive patients (and assertive parents) generate better health outcomes than passive ones. Take charge! The discomfort of annoying doctors and other hospital staff for a few minutes is minuscule compared to the offsetting years of health that might hang in the balance.

A first-person account of B. Cepacia:

Burkholderia Cepacia is another bacteria commonly found in the environment. Unfortunately it is more difficult to treat when PWCF get it in their lungs because it is resistant to some and potentially all antibiotics currently available. Generally patients’ health declines more rapidly after being colonized with b. cepacia. Also, I believe it is generally found in adult patients and or patients with more severe lung disease. I’ve had b. cepacia about 3 « years and have noticed a quicker decline in health over this time. I am currently waiting for a lung transplant to be done at U. of Minnesota. I have also speculated that I picked up the cepacia in the hospital when I was put in a room with another PWCFWC. My doc’s say I had it before then, but I don’t recall them ever telling me. Now, I am put in respiratory isolation when in the hospital.

On B. Cepacia in the environment:

Burkholderia cepacia is an anomalous organism. It has been found to be resistant to many antibiotics – there is one much cited report where it was found to grow on a bacteriological medium where Penicillin B was its only food source. It has also been shown to survive and even grow in certain types of disinfectants (in one case it survived in a salt solution containing a dilute disinfectant for 14 years). On the other hand it can be a very delicate organism. Grow it up on a standard bacteriological plate and within days of its attaining its full growth (reach its stationary phase), it be dead i.e. it will be impossible to sub-culture it from that plate. Under the same conditions P. aeruginosa could be recovered at least up to a week. Labs are usually unable to isolate cepacia from proven contaminated sputum specimens, if such specimens are stored overnight at 4’C (often normal practice in a busy lab). It is very sensitive to drying out. A surface contaminated by a sneeze for example will cease to yield viable cepacia within an hour (and it may be within minutes). This is unlike P. aeruginosa for example where it is reported that organism can be grown from dried sputum up to seven days after drying.

At the present, no one knows what is the major source of environment cepacia infection and therefore one cannot give definitive advice of what to avoid if you are at risk. However, it seems likely that a major source of environmental cepacia infection may arise from inhaling contaminated water aerosols (There maybe an analogy here with Legionella – the organism that causes the much publicized Legionnaires Disease. Strangely enough one cannot recall ever hearing of a PWCF who has contracted Legionella). If this is correct, avoiding exposure to water aerosols where contaminated water could be used (i.e. humidifiers and Mist tents) may reduce the risk for the PWCF. There have been reports that non CF people have contacted short term P. aeruginosa lung infections after using communal Jacuzzi so that would also be a source to avoid. Also for what it is worth another group of patients at risk from B. cepacia infection are immuno-compromised patients. Following their implications as a source of infection, flowers are now ban from the special care wards for such patients (in the UK at least).

It should be stressed however, that the risk of acquiring cepacia from the environment is believed to be very low. Based on experience in Wales, the acquisition rate since 1988 when they first started looking for cepacia, is about 1 new case every two years. Of course the risk can vary from place to place. A study from Philadelphia found that an environmental strain type was the major type isolated from their CF patients. However it is not clear, how much of the transmission of that strain was still patient to patient. (It is interesting that the first well documented report on Legionnaires Disease arose out of a study of an outbreak of a respiratory illness in the participants to the American Legion Convention held in Philadelphia). As to a source of cepacia being from onions: Cepacia was first isolated in 1950 by Burkholder from rotting onions (such onions are black and smell foul). It has also be isolated on occasion from soil and rotting tree trunks.

On B. Cepacia and gatherings of CF patients:

Following text is excerpted from two Canadian CF Foundation’s disclaimers published in 1994:

“… evidence to date strongly suggests that CF camps carry an unacceptably high risk of cross-infection with B. cepacia. The members of the Medical/Scientific Advisory Committee are extremely sensitive to the many benefits which CF camps offer, and deeply reluctant to see any young person with CF forego the camp experience. However, they are now convinced that the risks currently outweigh the benefits…

It is very much hoped that this suspension of involvement with camps will be a temporary measure, and that improved methods of detecting B. cepacia may, in future, at least allow for separate camps for colonized and non-colonized individuals.”

The next disclaimer soon followed. Clinics are asked by the CCFF to post it if a meeting is held with PWCF:

“Some people with CF might attend this meeting. Some of them might have an infection with Burkholderia cepacia, a bacteria that can be transmitted between people with CF. Health of those people with CF might decline following such an infection.

We believe that PWCF don’t run an important risk of being infected with Burkholderia cepacia by attending meetings that might be attended by others who are infected. Nevertheless, we strongly recommend to PWCF to avoid any prolonged and intimate contact with other PWCF.

Any persons attending this meeting do so at their own risk, and the Canadian CF Foundation does not assume responsibility relative to any health condition that might be influenced by this meeting or any social contact between PWCF.

For more information, please contact the director of your CF clinic or the CCFF head office.”

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Methicillin-Resistant Staphylococcus Aureus (MRSA)

MRSA stands for methicillin resistant staphylococcus aureus (although I have also seen it used for the synonymous Multi-resistant staphylococcus aureus). In both incidences it describes Staph aureus that is resistant to the normal antibiotics of choice. Strangely enough (bearing in mind the high incidence of S. aureus and the amount of antibiotic treatments taken by your average PWCF) it is still relatively rare in CF. I recently did a literature search and found no comprehensive studies on MRSA in CF which almost certainly means it is not common world wide. In our own experience, only two of our patients have had MRSA in the last 15 years. In both cases the infections were successfully treated with Vancomycin. This is one of the antibiotics we hold in reserve and only use to treat emerging multi-resistant organisms. Teicoplanin is another antibiotic that can be used in its treatment. Unlike B. cepacia, and P. aeruginosa, MRSA can usually be successfully removed and is not an infection that once got is usually for life. Of course there is no guarantee, that once it has been eradicated, a PWCF will not pick up either normal Staph or MRSA again at a later date.

For articles about MRSA and global nature of infection control, and on strict control measures enacted to fight MRSA, see Appendix L, Longer Articles.

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Stenotrophomonas maltophilia (10/97)

Previously known as Pseudomonas maltophilia then Xanthomonas maltophilia it is now called Stenotrophomonas maltophilia. Because it is resistant to a wide spectrum of antibiotics, and use of new isolation media indicate that its incidence in PWCF maybe higher than originally thought (5-7%), it has become a cause for concern in some quarters. However it appears that no recent studies (some of which were reported to the EWGCF meeting in Brussels in the summer of 1995) have shown convincingly that even long term carriage contributes to pulmonary problems unlike P. aeruginosa or B. cepacia.

Another description: It is fairly resistant to most antibiotics and is therefore often difficult to treat. In this respect it is very similar to B. cepacia as is the incidence of about 5% in PWCF and that the patient to patient infectious route is the main route of infection acquisition. There are well documented cases of it being mistaken as B. cepacia in some Microbiological labs – I have had personal experience of a S maltophilia being sent to me as a B cepacia isolate. However there the similarity seems to stop. Although many people have tried to show that S. maltophilia is a virulent pathogen in the CF lung, there is really little evidence that it contributes towards pulmonary deterioration. As far as I know there has been no reported cases of rapid and possible fatal decline in lung function on acquisition of S maltophilia unlike B. cepacia. There are anecdotal reports of acute infections in individual patients but when examine it is usually found that these patients are already carry other organisms such a P. aeruginosa, mycobacteria or aspergillus which could be causing the problems.

A review about maltophilia is: R. C. Spencer, “The emergence of epidemic, multi-antibiotic-resistant S. maltophilia and B. cepacia”, Journal of Hospital Infection (1995), Vol. 30 (Supplement) pp 435-64. This review is not directed solely at CF. The major complication with S. maltophilia is not in CF but in immune compromised patients.

The antimicrobial of choice in one clinic is Septrin to which the isolates were/are sensitive. In fact sensitivity to Septrin is used a diagnostic marker in S.maltophilia identification in that clinical laboratory.

One doctor said: “I think there is still a question concerning the role if any S.maltophilia infection might play in the developing pathogenesis of the lung in CF. In a recent review on S. maltophilia in CF by M Denton in Reviews in Medical Microbiology (1997) 8:15-19, I felt the author was hard pressed to justify the title of the review “Stenotrophomonas maltophilia: an emerging problem in cystic fibrosis patients” without the inclusion of a question mark.

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Aspergillosis

Aspergillosis is a mycotic (fungal) disease (it causes an allergic reaction which causes swelling in the bronchi) caused by species of the fungus Aspergillus. Although many of these species can cause disease in humans, the responsible organism is invariably Aspergillus fumigatus. Aspergillus are ubiquitous (means everywhere) in nature and occur in the upper respiratory tract. The organisms are found more commonly in the sputum of patients with bronchial asthma than in the general population. In one series, its isolation was considered more than coincidental in 50% of cases studies.

The Causative Organism: Conclusive diagnosis of Aspergillosis may be strongly suspected if this organism and no other organisms (except for those usually associated with chronic colonization and CF) can be cultured repeatedly from the sputum. Infections caused by Aspergillus may be divided into “primary” and “secondary” with primary infection representing the invasion of tissues in a previously healthy person without chronic systemic disease and secondary meaning an infection superimposed upon a condition that has already reduced host resistance (e.g., asthma & CF).1

Primary Aspergillosis:

Primary infection with Aspergillus is exceedingly rare. In most of the few reported instances of aspergillosis in otherwise healthy person there was no history of exposure. Clinically, the patient presents with infection, low grade fever, cough, and sometimes purulent sputum, hemoptysis and chest pain.

Secondary Aspergillosis: Usually there are little matted hyphae (fungus balls) that infect the pulmonary cavity. In the great majority of case, the fungus is present as a pure saprophyte (means the fungus derives it food from dead organisms (like cells and mucus in the CF lung). And almost invariably the underlying diseases in this case would be asthma, CF, bronchiectasis, chronic bacterial abscess (et al.). The diagnosis can be made by 3 means: (1) X ray in advanced cases; (2) bronchial biopsy of lung tissue; (3) cultures of sputum but this is the least reliable as few patients with this form of aspergillus (secondary kind) can expectorate this fungus. A 4th indicator is a skin test yet this only shows the presence of the antigen, and does not demonstrate aspergillosis. It only confirms that your body has come into contact with this fungus at sometime in your recent past. Clinically, most patients with Secondary Aspergillosis are healthy. Cough and expectoration are common; hemoptysis has been reported in up to 70& of the cases.2

Aspergillosis with Chronic Debilitating Disease: In patients with impaired host defenses, aspergilli may spread through out the chest cavity and into other parts of the body. Almost all patients with this type of spreading aspergillus have a malignancy or have undergone an organ transplant.3 Patients in this category typically have unremitting fever which responds poorly or not at all to antibiotic therapy.

Treatment Aspergillus fumigatus is best treated with corticosteroids and other anti-asthmatic drugs (aminophylline/expectorants) which is usually successful in allowing expectoration of the mucus plugs and with them, Aspergillus fungus. Prednisone treatment may be needed for long term treatment. Immunotherapy and fungicidal or fungistatic agents are not recommended. Allergy shots with extracts of Aspergillus fumigata is contraindicated since it produces bothersome local reactions and may cause an exacerbation of symptoms.

References cited: 1 Campbell, M.J., and Clayton, Y.M.: Bronchopulmonary aspergillosis. A correlation of the clinical and laboratory findings in 272 patients investigated for bronchopulmonary aspergillosis. American Review of Respiratory Disease, Volume 89, Number 186. 2 Levin, E. J.: Pulmonary intercavitary fungus ball. Radiology, 66:9, 1956 3 Meyer, R.D., Young, L.S. Armstrong, D., and Yu, B.: Aspergillosis complicating chronic disease. American Journal of Medicine, 54:6, 1973

How Does Construction Increase Risk of Aspergillosis?

Infection control practitioners at hospitals undergoing construction or renovation should ensure adequate air quality precautions are in place and strictly enforced to prevent deadly outbreaks of aspergillosis. For an article on this, see Appendix L, Longer Articles.

First-Person Accounts of Aspergillosis:

So sorry to hear that your daughter’s not doing well. Have your docs tried IV anti-fungals, or do they feel that her Hepatitis A precludes use of these? We’ve had only two patients ever who developed the “classic” allergic bronchopulmonary aspergillosis (ABPA), but they both had symptoms just like your daughter’s, and both responded to amphotericin (the only anti-fungal we had available at the time; now there are other less toxic drugs than “amphoterrible”). Other patients haven’t been quite so bad, and responded to the steroids without need for antifungals. The weight loss, dry and nonproductive cough, fatigue, breathlessness, and lack of response to regular antibiotics are the key here, and her known sensitivities to Aspergillus make the diagnosis even more probable. We pulled in the infectious disease docs and let them do the dosing, as they are more used to handling these antifungals and hepatitis and the whole lot. That’s my main recommendation–pull in the infectious disease people. Also remember that just because there may not be fluffy fungus balls visible on X- ray or an IgE greater than 1000 (parts of the classic definition of ABPA), she can still have the “CF” version of ABPA; we’ve only once seen the fluff balls, but we’ve treated a lot of patients with rising IgE levels, positive response to Aspergillus antigens, and the symptoms you note. And they didn’t get better until we used the steroids and/or antifungals, despite weeks of IV antibiotics, chest PT, etc.

Just from a layman’s view (and I had some horrible times battling good old aspergillus), when I had trouble with aspergillus, I could see different colors in my sputum (Yick!); sometimes spots of gray or brown, but most often it just sort of had an orange or pink cast to it. Actually kinda pretty in a disgusting way. It did give me terrible asthma though. I was put on Sporanox (Itraconazole) to help, it kills the stuff supposedly, but it didn’t really help much. The only relief I got was on big doses of steroids.

My daughter was also just prescribed flovent for her resolving aspergillus problem. She had been on prednisone over the last year (small dose), which helped immensely. The nice thing about flovent is it has powerful effects on the lung but apparently it is hardly absorbed systemically (or so the literature states).

The reason my CF doc wanted me to try Flovent was because it apparently has way less systemic side effects than either Becloforte/Beclovent and also Pulmicort. Like my message said, the price is crazy for 1 small inhaler ($138).

If I see a non-productive, dry and hacking cough in an adult, I right away check sputum samples and skin tests for Aspergillus. When this fungus flares up, most people get a dry, hacky or tickle cough; feel fatigued; often lose weight. And all the antibiotic therapies usually done don’t help, since it’s a fungus. We use a prednisone burst, which is a week or two of prednisone, starting with lots for the first three days then rapidly tapering down to none at all. If people have chronic problems with this, we use steroid inhalers. There are blood tests which will show if the body is reacting to a fungus: hypersensitivity tests, which tell you which agents your body reacts to, and the IgE, which is non-specific but tells you the immune system is turned on. I don’t know how prevalent these fungal things are in little ones, but it’s an idea.

We also use cough medicine (the STRONG stuff, if needed) for night-time only. If you’re coughing all the time and never get any sleep, sooner or later you end up in the hospital because you’re too fatigued to clear your lungs. Much better to get a good night’s sleep and then do intensive secretion clearance all day to get the gunk out.

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